Pharmaceutical combination, composition and compound preparation containing glucokinase activator and k-atp channel blocker, preparation method therefor and use thereof

ABSTRACT

The present invention relates to a pharmaceutical combination, the pharmaceutical combination comprising a glucokinase activator or a pharmaceutically acceptable salt thereof, an isotopic label thereof, a crystal form thereof, a hydrate, a solvate, a diastereomer or enantiomer, and a K-ATP channel blocker. The present invention further relates to a pharmaceutical composition, a fixed dose compound preparation, and a method for preparing the pharmaceutical composition and the fixed dose compound preparation as well as a use thereof.

PRIORITY APPLICATION

This application claims the priority of the Chinese patent applicationNo. 201810556685.6 filed on May 31, 2018, the entire disclosure of whichis incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to a pharmaceutical combination, acomposition and a fixed dose combination (FDC) formulation comprising aglucokinase activator (GKA) drug and a partner drug, to a preparationmethod thereof and to a use thereof in the treatment of some diseases.

More specifically, the present disclosure relates to a pharmaceuticalcombination, a pharmaceutical composition, or an oral solid formulationof a fixed dose combination comprising a glucokinase activator drug anda partner drug, and a preparation method thereof. The present disclosurealso relates to the use of a pharmaceutical combination, apharmaceutical composition or a fixed dose combination formulationcomprising a glucokinase activator for the treatment and/or preventionof one or more diseases and medical disorders, including but not limitedto type I diabetes, type II diabetes, maturity-onset diabetes of theyoung (MODY), diseases associated with islet dysfunction, impairedglucose tolerance, impaired fasting blood glucose, obesity andhypertension. In addition, the present disclosure also relates to amethod for treating and/or preventing one or more diseases and medicaldisorders, comprising administering a therapeutically effective amountof the pharmaceutical combination, pharmaceutical composition or fixeddose combination formulation disclosed herein to a subject in needthereof.

BACKGROUND

Diabetes mellitus has become a prevalent disease worldwide, with 425million patients over the world, and 120 million patients in China(International Diabetes Federation, Diabetes Atlas, 2015). Type IIdiabetes, i.e., non-insulin dependent diabetes mellitus (NIDDM),accounts for more than 90% of the patients with diabetes. Type IIdiabetes is a hyperglycemic, chronic, metabolic dysfunction resultingfrom an imbalance of blood glucose homeostasis in human body caused byinsulin secretion disorder and insulin resistance. The blood glucosebalance of the human body is mainly coordinated by two hormones thatcontrol blood glucose, including insulin and glucagon.

Glucose sensor glucokinase (GK) senses blood glucose changes, regulatesthe secretion of the messenger glucose-controlling hormones, insulin andglucagon, and GLP-1 (glucagon-like peptide-1), and constitutes a sensingsystem for steady-state regulation of human blood glucose.Glucose-controlling hormones control glucose storage during glucoseuptake and glucose supply during fasting, constituting the steady-stateregulation of human blood glucose. Organs involved in glucose storageare mainly liver, muscle and fat. Under the action of blood glucose andinsulin, glucose is taken up and converted into liver glycogen, muscleglycogen and triglycerides. The main organ involved in glucose supply isliver. Under the action of blood glucose and glucagon, liver suppliesglucose to a human body through liver glucose synthesis and liverglucose output. Insulin can also effectively regulate the activity ofsodium-glucose cotransporter SGLT-2. When blood glucose rises, theglucose excreted by kidneys is reabsorbed for body's glucose storage.Glucose uptake and liver glucose output, as well as the use of glucoseby various organs, constitute an operating system for a steady-statebalance of the human blood glucose. The coordinated operation of thesensing system and the operating system of glucose constitute a randomregulation of a steady-state of the human blood glucose.

In diabetic patients, the impaired function and expression ofglucokinase, and the dysfunction of the sensor, result in thedysfunction of the early phase secretion of glucose-controllinghormones, affecting glucose uptake and output, and resulting inpost-prandial hyperglycemia and pre-prandial hypoglycemia. Abnormalsignaling of glucose-controlling hormones cause abnormal functions andexpressions of key proteins in the execution system of glucose uptakeand output, forming abnormal operating state, leading to type IIdiabetes.

Existing oral hypoglycemic drugs for diabetes usually act on a singleglucose-controlling organ and cannot effectively treat the problem ofimbalanced blood glucose homeostasis. Glucokinase activators represent aclass of new drugs developed to treat or improve the disease state ofpatients with type II diabetes. For example,((S)-2-[4-((2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoicacid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (referred toas HMS5552 hereinafter) can effectively improve the function of theglucose sensor in diabetic patients, and is currently the most promisingdrug for the treatment of diabetes to solve the above clinical needs.

SUMMARY

Diabetic patients often encounter such a situation during treatment thatK-ATP channel blockers alone are not effective, and blood glucose cannotbe controlled to an ideal level, especially after a period of use. Inthis regard, the inventors found that the combination of a K-ATP channelblocker and a glucokinase activator can significantly improve thehypoglycemic effect of the K-ATP channel blocker and reduce the safetyrisk, thus the pharmaceutical combination, composition and combinationformulation comprising a glucokinase activator and a K-ATP channelblocker disclosed herein were obtained.

More specifically, the combination of a K-ATP channel blocker and aglucokinase activator can improve the function of multiple organs ofpatients in middle and late stages, and diabetes and accompanyingdiseases and complications were well treated. The number of pills takenby patients was reduced and the compliance of patients was improved, thetotal dose of drugs that achieve the same therapeutic effect wasreduced, and the maximum efficacy was achieved with the lowest dose. Ithas a good effect and practical significance for the treatment orprevention of one or more of type I diabetes, type II diabetes,hyperglycemia, impaired glucose tolerance, obesity and other symptoms.

On the other hand, the fixed dose combination formulation comprising aglucokinase activator and a partner drug (the second or more activepharmaceutical ingredients) disclosed herein not only has bettertherapeutic effects than the single use of each of these two or moredrugs, but also solves the technical challenges that usually exist incombination formulations. The fixed dose combination formulationdisclosed herein can provide the simultaneous release of two or moreactive ingredients with uniform content, and can optimize thedissolution rate of active ingredients contained in the formulation,especially making the active ingredients contained in the formulationquickly released in the pH environment of a small intestine. This isbeneficial to the timely or simultaneous arrival of drugs in gut,pancreatic islet and liver target organs, achieving clinical advantagesof multi-organs targeting, and synergistic hypoglycemic effect, andexhibiting a better therapeutic effect and reduced toxic or sideeffects. In addition, the fixed dose combination formulation comprisinga glucokinase activator and a partner drug (the second or more activepharmaceutical ingredients) disclosed herein also has a shortdisintegration time, and good dissolution characteristics, and/or giveshigh bioavailability of the glucokinase activator in patients.

The present disclosure provides a pharmaceutical combination, apharmaceutical composition, and a fixed dose combination formulationcomprising a glucokinase activator, such as HMS5552 with the followingstructure, or an isotope labeled analogue thereof, or a pharmaceuticallyacceptable salt thereof, and other oral hypoglycemic drug, especially asolid formulation, such as an oral solid formulation such as a tablet,

Specifically, the present disclosure also provides a pharmaceuticalcombination, a pharmaceutical composition, or a fixed dose combinationformulation comprising a glucokinase activator drug such as HMS5552 or apharmaceutically acceptable salt thereof and a K-ATP channel blockerincluding sulfonylurea secretagogues and non-sulfonylurea insulinsecretagogues. Among them, preferably, examples of the sulfonylureasecretagogues include, but are not limited to, glibenclamide, glipizide,gliclazide, gliquidone and glimepiride, and a pharmaceuticallyacceptable salt thereof; and examples of the non-sulfonylurea insulinsecretagogues include repaglinide and nateglinide, and apharmaceutically acceptable salt thereof.

More specifically, the present disclosure also provides a fixed dosecombination solid formulation comprising a glucokinase activator drugsuch as HMS5552 or a pharmaceutically acceptable salt thereof and apartner drug such as glimepiride. The solid formulation is preferably atablet, or more preferably a coated tablet. In one embodiment, theglucokinase activator HMS5552 is in the form of a solid dispersioncontaining a polymer carrier.

More specifically, the present disclosure also provides a fixed dosecombination solid formulation comprising a glucokinase activator drugsuch as HMS5552 or a pharmaceutically acceptable salt thereof and apartner drug such as repaglinide. The solid formulation is preferably atablet, or more preferably a coated tablet. In one embodiment, theglucokinase activator HMS5552 is in the form of a solid dispersioncontaining a polymer carrier.

The present disclosure also provides a pharmaceutical combination, apharmaceutical composition or a fixed dose combination formulation of aglucokinase activator drug and a partner drug (the second or more activepharmaceutical ingredients) prepared by a dry or wet processing method.The release mode of the pharmaceutical combination, pharmaceuticalcomposition or fixed dose combination formulation disclosed herein israpid release of the two or more active pharmaceutical ingredients.

The present disclosure also provides a pharmaceutical formulationcomprising a glucokinase activator drug and a partner drug (the secondor more active pharmaceutical ingredients), which has a shortdisintegration time and good dissolution characteristics and/or giveshigh bioavailability of the glucokinase activator in patients. Thepresent disclosure also provides a method of preparing a pharmaceuticalcomposition or a pharmaceutical formulation of a fixed dose combinationof a glucokinase activator drug and a partner drug (the second or moreactive pharmaceutical ingredients, such as glimepiride or repaglinide)by a dry or wet processing method. The dry processing method includesdry compression (tableting) and dry granulation; and the wet processingmethod includes wet granulation.

The present disclosure also provides a pharmaceutical combination, apharmaceutical composition or a pharmaceutical formulation comprising aglucokinase activator drug and a partner drug (the second or more activepharmaceutical ingredients), and a method for preventing, slowing down,delaying or treating a metabolic disorder (especially type II diabetes).

The present disclosure also provides a pharmaceutical combination, apharmaceutical composition or a pharmaceutical formulation comprising aglucokinase activator drug and a partner drug (the second or more activepharmaceutical ingredients), and a method for improving blood glucosecontrol in patients in need thereof, especially patients with type IIdiabetes.

The present disclosure also provides a pharmaceutical combination, apharmaceutical composition or a pharmaceutical formulation comprising aglucokinase activator drug and a partner drug, and a method forimproving blood glucose control in patients with insufficient bloodglucose control.

The present disclosure also provides a pharmaceutical combination, apharmaceutical composition or a pharmaceutical formulation comprising aglucokinase activator drug and a partner drug, and a method forpreventing, slowing down or delaying maturity-onset diabetes of theyoung (MODY), diseases associated with islet dysfunction, impairedglucose tolerance (IGT), impaired fasting blood glucose (IFG),hypertension, insulin resistance and/or progression of metabolicsyndrome to type II diabetes.

The present disclosure also provides a pharmaceutical combination, apharmaceutical composition and a pharmaceutical formulation comprising aglucokinase activator drug and a partner drug, and a method forpreventing, slowing down, delaying or treating a disease or a disorderincluding diabetes complications.

Other objects of the present disclosure will be apparent to thoseskilled in the art from the description and examples.

BRIEF DESCRIPTION OF THE EMBODIMENTS

The first aspect of the present disclosure provides a pharmaceuticalcombination, a pharmaceutical composition or a pharmaceuticalformulation comprising the following components, a preparation methodthereof, and a use thereof for treating diabetes and related diseases:

-   (a) a glucokinase activator, which is a compound selected from the    following formula, or a pharmaceutically acceptable salt, an isotope    labeled analogue, a crystalline form, a hydrate, a solvate, a    diastereomeric or enantiomeric form thereof; preferably, the    glucokinase activator is HMS5552; or more preferably, HMS5552 is    present in the form of a solid dispersion,

-   (b) a K-ATP channel blocker; and-   (c) one or more excipients.

Another aspect of the present disclosure provides a pharmaceuticalcombination, a pharmaceutical composition or a pharmaceuticalformulation comprising the following components, a preparation methodthereof, and a use thereof for the treatment of diabetes and relateddiseases:

-   (a) a glucokinase activator, which is HMS5552 compound, or a    pharmaceutically acceptable salt, an isotope labeled analogue, a    crystalline form, a hydrate, a solvate, a diastereomeric or    enantiomeric form thereof; preferably, the glucokinase activator is    HMS5552; more preferably, HMS5552 is present in the form of a solid    dispersion;-   (b) glimepiride, repaglinide, or a pharmaceutically acceptable salt,    an isotope labeled analogue, a crystalline form, a hydrate, a    solvate, a diastereomeric or enantiomeric form thereof; and-   (c) one or more excipients.

In particular, one aspect of the present disclosure also relates to apharmaceutical combination, a pharmaceutical composition, and apharmaceutical formulation comprising a fixed dose combination of aHMS5552 solid dispersion and a partner drug (e.g., glimepiride,repaglinide), and a preparation method thereof and a use thereof.

Definition

Unless otherwise specified, all technical and scientific terms usedherein have the same meanings as commonly understood by those skilled inthe art to which the present disclosure belongs, but in case ofconflict, the definitions in this specification shall prevail.

As used in the specification and claims, the singular forms “a”, “an”and “the (said)” include plural forms, unless the context clearlydictates otherwise.

Unless otherwise specified, the percentages (%) in the specification areall weight percentages (% by weight).

All numerical values or expressions related to component amounts,process conditions, etc. used in the specification and claims should beunderstood to be modified by “about” in all cases. The term “about” whenreferring to a quantity or a range of numerical values means that thequantity or the range of numerical values referred to is an approximatevalue within experimental variability (or within statisticalexperimental error). Therefore, the quantity or the range of numericalvalues can be varied between, for example, ±5 percent of the quantity orthe range of numerical values.

All ranges involving the same components or properties includeendpoints, which can be independently combined. Since these ranges arecontinuous, they include every value between the minimal and maximalvalues. It should also be understood that any numerical range cited inthis application is intended to include all sub-ranges within thatrange.

When the present disclosure uses a range to define physical propertiessuch as molecular weight or chemical properties, it shall include allcombinations and sub-combinations of the range and specific embodimentstherein. The term “comprising” (and related terms such as “containing”or “including” or “having”) includes embodiments which are, for example,any combinations of substances, compositions, methods, or processes,etc., and are “consisted of the described features” or “essentiallyconsisted of the described features”.

As used in the specification and claims, “and/or” should be understoodas “one or both” of the associated components, that is, the componentscoexist in some cases and exist separately in other cases. Multiplecomponents listed with “and/or” should be understood in the same way,that is, “one or more” of the associated components. In addition to thecomponents specifically identified in the “and/or” clause, othercomponents may optionally be present, whether associated or notassociated with those specifically identified components. Therefore, asa non-limiting example, when “A and/or B” is used to connect an openending word such as “comprising”, in one embodiment, it may only referto A (optionally comprising components other than B); in anotherembodiment, it can only refer to B (optionally comprising componentsother than A); in yet another embodiment, it refers to A and B(optionally comprising other components), etc.

It should be understood that, unless explicitly indicated to thecontrary, in any method that includes more than one step or one actclaimed herein, the order of the steps and acts of the method is notnecessarily limited to the order of the steps and acts of the methoddescribed.

The abbreviations used in the present disclosure have the commonmeanings in the fields of chemistry, biology and formulation.

Unless otherwise specified, the term “K-ATP channel blocker” or anysubstance thereof (e.g., “glimepiride”, “repaglinide”) in the context ofthe present disclosure is also intended to include any pharmaceuticallyacceptable salt, crystalline form, hydrate, solvate, diastereomer orenantiomer thereof.

HMS5552 (its former name is R05305552, and English name is Dorzagliatin)has a chemical name of(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoicacid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide.

Unless otherwise specified, % by weight (wt %) represents a percentageof the total weight of a pharmaceutical combination, a pharmaceuticalcomposition or a pharmaceutical formulation.

A solid dispersion (SD) refers to a solid dispersion system formed byhighly dispersing one or more active pharmaceutical ingredients intoinactive adjuvants or carriers.

EUDRAGIT is the trade name of a synthetic pharmaceutical adjuvant. Itincludes copolymers of methacrylic acid and copolymers of methacrylateester, collectively referred to as polyacrylic resins. Adjuvants basedon polyacrylic resin are divided into different models according totheir composition, proportion and degree of polymerization. Among them,Eudragit E is a polymer of dimethylaminoethyl methacrylate andmethacrylate; Eudragit L is a polymer of methacrylic acid and methylmethacrylate with free carboxyl:ester of 1:1; and Eudragit S is apolymer of methacrylic acid and methyl methacrylate with freecarboxyl:ester of 1:2.

The term “tablet” as used herein is intended to include compressedpharmaceutical formulations of all shapes and sizes, whether coated ornot.

The terms “effective amount” or “therapeutically effective amount” referto an amount of the agent sufficient to provide the desired biologicalresult. The biological result may be a reduction and/or alleviation ofthe signs, symptoms, or causes of a disease, or any other desiredalteration of a biological system. For example, an “effective amount”for therapeutic use is the necessary amount of the compositioncomprising a compound as the active ingredient as disclosed herein forproviding a clinically significant decrease in a disease. An appropriate“effective” amount in any individual embodiment may be determined by oneof ordinary skill in the art using routine experimentation. Thus, theexpression “effective amount” generally refers to the quantity for whichthe active substance has therapeutic effects.

As used herein, the terms “treat” or “treatment” are synonymous with theterm “prevent” and are meant to indicate a postponement of developmentof diseases, preventing the development of diseases, and/or reducingseverity of such symptoms that will or are expected to develop. Thus,these terms include ameliorating existing disease symptoms, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, inhibiting the disorder or disease, e.g., preventingthe development of the disorder or disease, relieving the disorder ordisease, causing a regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

By “pharmaceutically acceptable” or “pharmacologically acceptable”, itis meant a material which is not biologically or otherwise undesirable,i.e., the material may be administered to an individual without causinga minimum of undesirable biological effects or interacting in adeleterious manner with any other components of the composition in whichit is contained.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of themammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentdisclosure, the mammal is a human.

A compound as an active ingredient in a pharmaceutical combination, apharmaceutical composition or a pharmaceutical formulation (e.g., afixed dose combination formulation) comprising a glucokinase activatordisclosed herein may form a salt. Reference to a compound disclosedherein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as used herein, denotes acidicsalts formed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundcontains both a basic moiety, such as, but not limited to a pyridine orimidazole, and an acidic moiety, such as, but not limited to acarboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundmay be formed, for example, by reacting the compound with an amount,such as an equivalent amount, of acid or base in a medium such as amedium from which the salt precipitates or in an aqueous medium(lyophilization after reaction).

Various compounds and salts, solvates, esters and prodrugs thereof, andpolymorphs thereof are intended to be included in the disclosure.

It is to be understood that the terminology employed herein is for thepurpose of describing particular embodiments, and is not intended to belimiting. Further, although any methods, devices and materials similaror equivalent to those described herein can be used in the practice ortesting of the invention, the preferred methods, devices and materialsare described below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect on blood glucose after glucose challenge innormal mice (X±s, n=10) with the administration of repaglinide alone andthe combination of HMS5552 and repaglinide; and

FIG. 2 shows the effect on AUC₀₋₁₂₀ min after glucose challenge innormal mice (X±s, n=10; ***, P<0.001) with the administration ofrepaglinide alone and the combination of HMS5552 and repaglinide.

DETAILED DESCRIPTION OF THE EMBODIMENTS

One aspect of the present disclosure relates to a pharmaceuticalcombination, a pharmaceutical composition or a pharmaceuticalformulation such as a fixed dose combination formulation of aglucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof) and a partnerdrug (e.g., glimepiride, repaglinide). The formulation can be powder,granule, tablet, capsule, sachet or other solid forms. Specifically, oneaspect of the present disclosure relates to a tablet comprising a fixeddose combination of a glucokinase activator and a partner drug (e.g.,glimepiride, repaglinide).

In a specific aspect of the present disclosure, the pharmaceuticalcombination, pharmaceutical composition or pharmaceutical formulationcomprises:

(1) a glucokinase activator or a pharmaceutically acceptable saltthereof, or an isotope labeled analogue, a crystalline form, a hydrate,a solvate, a diastereomeric or enantiomeric form thereof; preferably,the glucokinase activator is HMS5552; more preferably, HMS5552 ispresent in the form of a solid dispersion, such as a solid dispersion(e.g., a spray-dried powder) comprising a polymer carrier;(2) a K-ATP channel blocker; preferably selected from: glimepiride,repaglinide, or a pharmaceutically acceptable salt, an isotope labeledanalogue, a crystalline form, a hydrate, a solvate, a diastereomeric orenantiomeric form thereof; and/or(3) filler(s); and/or(4) binder(s); and/or(5) disintegrant(s); and/or(6) lubricant(s) or glidant(s); and/or(7) coating agent(s).

In one embodiment disclosed herein, the pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation may alsocontain one or more excipients selected from the group consisting of oneor more binders; one or more diluents (fillers); one or moredisintegrants; one or more lubricants; one or more glidants; one or moresurfactants or wetting agents; one or more antioxidants; and one or morecoating agents.

Pharmaceutical Combination, Pharmaceutical Composition, orPharmaceutical Formulation Glucokinase Activator+K-ATP Channel Blocker

In one embodiment, the present disclosure relates to a pharmaceuticalcombination, a pharmaceutical composition, or a pharmaceuticalformulation (preferably, a fixed dose combination formulation), whichcomprises:

(a) a glucokinase activator, which is a compound represented by thefollowing formulae, or a pharmaceutically acceptable salt, an isotopelabeled analogue, a crystalline form, a hydrate, a solvate, adiastereomeric or enantiomeric form thereof,

(b) a K-ATP channel blocker,preferably, the K-ATP channel blocker includes sulfonylurea insulinsecretagogues and non-sulfonylurea insulin secretagogues; wherein thesulfonylurea insulin secretagogues include glibenclamide, glipizide,gliclazide, gliquidone and glimepiride, and the non-sulfonylurea insulinsecretagogues include repaglinide and nateglinide; preferably,glimepiride and repaglinide; and(c) one or more excipients;wherein the above-mentioned drugs (a) and (b) are used simultaneously,separately or sequentially.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), the weight ratio of the glucokinaseactivator to the K-ATP channel blocker is about 400:1 to 10:1,preferably about 100:1 to 25:2, or more preferably about 25:2, about25:1, about 50:1, about 75:2, about 75:1, or about 100:1.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), the glucokinase activator ispresent in a dose (preferably, a unit dose) ranging from about 1 mg toabout 200 mg, or preferably about 25 mg to about 100 mg, preferably,wherein the dose (preferably, a unit dose) of the glucokinase activatoris about 25 mg, about 50 mg, about 75 mg or about 100 mg.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation, the K-ATPchannel blocker is present in a dose (preferably, a unit dose) rangingfrom about 0.1 mg to about 10 mg, or preferably about 1 mg to about 5mg, preferably, wherein the dose (preferably, a unit dose) of the K-ATPchannel blocker is about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg,about 1.5 mg, about 2 mg, about 4 mg or about 5 mg, or still preferablyabout 1 mg or about 2 mg; and preferably, the K-ATP channel blocker isglimepiride or repaglinide.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), the above-mentioned glucokinaseactivator is the compound HMS5552, or an isotope labeled analogue, or apharmaceutically acceptable salt thereof,

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), the glucokinase activator ispresent in the form of a solid dispersion.

In one embodiment, the solid dispersion is obtained by spray drying, hotmelting or freeze drying of a glucokinase activator, or an isotopelabeled analogue, or a pharmaceutically acceptable salt thereof,together with a polymer carrier.

In one embodiment, the amount of the glucokinase activator in the soliddispersion, based on the total weight of the solid dispersion, may varyfrom about 1% to about 99% by weight, or preferably from 10% to 90% byweight. In one embodiment, the amount of the glucokinase activator isabout 1% by weight, about 2% by weight, about 3% by weight, about 4% byweight, about 5% by weight, about 6% by weight, about 7% by weight,about 8% by weight, about 9% by weight, about 10% by weight, about 11%by weight, about 12% by weight, about 13% by weight, about 14% byweight, about 15% by weight, about 16% by weight, about 17% by weight,about 18% by weight, about 19% by weight, about 20% by weight, about 21%by weight, about 22% by weight, about 23% by weight, about 24% byweight, about 25% by weight, about 26% by weight, about 27% by weight,about 28% by weight, about 29% by weight, about 30% by weight, about 31%by weight, about 32% by weight, about 33% by weight, about 34% byweight, about 35% by weight, about 36% by weight, about 37% by weight,about 38% by weight, about 39% by weight, about 40% by weight, about 41%by weight, about 42% by weight, about 43% by weight, about 44% byweight, about 45% by weight, about 46% by weight, about 47% by weight,about 48% by weight, about 49% by weight, about 50% by weight, about 51%by weight, about 52% by weight, about 53% by weight, about 54% byweight, about 55% by weight, about 56% by weight, about 57% by weight,about 58% by weight, about 59% by weight, about 60% by weight, about 61%by weight, about 62% by weight, about 63% by weight, about 64% byweight, about 65% by weight, about 66% by weight, about 67% by weight,about 68% by weight, about 69% by weight, about 70% by weight, about 71%by weight, about 72% by weight, about 73% by weight, about 74% byweight, about 75% by weight, about 76% by weight, about 77% by weight,about 78% by weight, about 79% by weight, about 80% by weight, about 81%by weight, about 82% by weight, about 83% by weight, about 84% byweight, about 85% by weight, about 86% by weight, about 87% by weight,about 88% by weight, about 89% by weight, about 90% by weight, about 91%by weight, about 92% by weight, about 93% by weight, about 94% byweight, about 95% by weight, about 96% by weight, about 97% by weight,about 98% by weight, or about 99% by weight, or any range therebetween.

In one embodiment, the amount of the glucokinase activator in the soliddispersion, based on the total weight of the solid dispersion, is about1% to about 20% by weight, about 2% to about 40% by weight, about 30% toabout 60% by weight, about 60% to about 80% by weight, about 70% toabout 90% by weight, or about 80% to about 100% by weight.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation), the glucokinase activator is thecompound HMS5552, an isotope labeled analogue thereof or apharmaceutically acceptable salt thereof, which is combined with apolymer carrier to obtain a solid dispersion by spray drying, hotmelting or freeze drying, etc.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation), the polymer carrier in the soliddispersion is selected from a polypropylene resin-based polymer, whichis a polymeric compound derived from the polymerization of acrylic acid(or methacrylic acid and esters thereof such as methyl ester, ethylesters and the like) (as monomer), or derived from the polymerization oftwo monomers (binary polymerization) or three monomers (ternarypolymerization) in a certain ratio using acrylic acid and methacrylicacid (or its ester such as methyl ester, ethyl ester, dimethylaminoethylester, etc.).

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), the glucokinase activator ispresent in the form of a solid dispersion, and the weight ratio of thesolid dispersion of the glucokinase activator to the K-ATP channelblocker is about 400:1 to 20:1, preferably about 200:1 to 25:1, or morepreferably about 25:1, about 50:1, about 100:1, about 75:1, about 150:1or about 200:1.

In one embodiment, the polymer carrier used in the solid dispersion inthe above-mentioned pharmaceutical combination, pharmaceuticalcomposition or pharmaceutical formulation (preferably, a fixed dosecombination formulation) is selected from the group consisting ofcopolymer of butyl methacrylate, dimethylaminoethyl methacrylate andmethyl methacrylate; copolymer of methacrylic acid and ethyl acrylate;copolymer of methacrylic acid and methyl methacrylate; copolymer ofethyl acrylate, methyl methacrylate and chlorotrimethylamino ethylmethacrylate; copolymer of ethyl acrylate and methyl methacrylate;copolymer of methacrylic acid, methyl acrylate and methyl methacrylate,and copolymer of methacrylic acid and butyl acrylate.

In one embodiment, the above-mentioned polymer carrier is selected fromthe group consisting of copolymer of butyl methacrylate,dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1),copolymer of methacrylic acid and ethyl acrylate (1:1), copolymer ofmethacrylic acid and methyl methacrylate (1:2), copolymer of ethylacrylate, methyl methacrylate and chlorotrimethylamino ethylmethacrylate (1:2:0.2), copolymer of ethyl acrylate, methyl methacrylateand chlorotrimethylamino ethyl methacrylate (1:2:0.1), copolymer ofethyl acrylate and methyl methacrylate (2:1), copolymer of methacrylicacid and butyl acrylate (35:65), copolymer of methacrylic acid andmethyl methacrylate (1:1), copolymer of methacrylic acid and methylmethacrylate (35:65).

In one embodiment, the above-mentioned polymer carrier is Eudragit,including Eudragit E, Eudragit L, Eudragit S, Eudragit RL and EudragitRS, wherein Eudragit E is produced by the polymerization ofdimethylamino methacrylate and other neutral methacryates, includingcopolymers of dimethylaminoethyl methacrylate and methacrylate; EudragitL and Eudragit S is produced by the polymerization of methacrylic acidand methacrylates in various ratios, including a copolymer ofmethacrylic acid and methyl methacrylate with 1:1 of free carboxyl:esteror a copolymer of methacrylic acid and methyl methacrylate with 1:2 offree carboxyl:ester; Eudragit RL and Eudragit RS type is a copolymer ofacrylic acid containing some quaternary amine groups and methacrylate,including the copolymer of acrylic acid containing 10% quaternary aminegroup and methacrylate and the copolymer of acrylic acid containing 5%quaternary amine group and methacrylate.

In one embodiment, the above-mentioned polymer carrier is selected fromthe group consisting of:

Eudragit E100, which is copolymer of butyl methacrylate,dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1),including Eudragit E PO;Eudragit L100, methacrylic acid copolymer of type A, which is an anioniccopolymer of methacrylic acid and methyl methacrylate (1:1); andEudragit S100, which is copolymer of methacrylic acid and methylmethacrylate (1:2).

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation), the polymer carrier in the soliddispersion of HMS5552 is methacrylic acid copolymer of type A (ananionic copolymer of methacrylic acid and methyl methacrylate (1:1)),preferably Eudragit, or more preferably Eudragit L100.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation), the weight ratio of HMS5552 toEudragit L100 in the solid dispersion of HMS5552 is about 1:10 to 10:1,about 1:9 to 9:1, about 2:3 to 9:1, about 3:4 to 9:1, about 4:5 to 9:1,about 5:6 to 9:1, or about 1:1 to 9:1; preferably, about 2:3 to 4:1,about 3:4 to 4:1, about 4:5 to 4:1, about 5:6 to 4:1, or about 1:1 to4:1; preferably, about 2:3 to 7:3, about 3:4 to 7:3, about 4:5 to 7:3,about 5:6 to 7:3, or about 1:1 to 7:3; preferably, about 2:3 to 3:2,about 3:4 to 4:3, about 4:5 to 5:4, or about 5:6 to 6:5; preferably,about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3,about 4:5 to 5:4, or about 5:6 to 6:5, or any range therebetween.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation), the weight ratio of HMS5552 toEudragit L100 in the solid dispersion of HMS5552 is about 1:1, about2:3, about 3:2, about 1:4, about 4:1, about 3:4, about 4:3, about 4:5,about 5:4, about 5:6, about 6:5, about 7:3, about 3:7, about 1:9, about9:1, or any range therebetween.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), the second active ingredient isglimepiride. The above-mentioned pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulation of theglucokinase activator (HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof) and glimepiride contains (byweight): about 1-99% of the glucokinase activator (preferably, HMS5552or an isotope labeled analogue or a pharmaceutically acceptable saltthereof); about 0.1-15% of glimepiride; about 0-85% of filler(s); about1-25% of binder(s); about 0-15% of disintegrant(s); about 0.1-10% oflubricant(s); about 0-3% of glidant(s); and about 0-5% of coatingagent(s). The pharmaceutical composition or pharmaceutical formulation(preferably, a fixed dose combination formulation) is prepared by a wetgranulation method or a dry granulation method, preferably by a wetgranulation method.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation) of the glucokinase activator(HMS5552 or an isotope labeled analogue or a pharmaceutically acceptablesalt thereof) and glimepiride, the dose (preferably, a unit dose) of theglucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof) is about 1 mg to200 mg. The preferable dose (preferably, a unit dose) of the glucokinaseactivator is about 5 mg to 100 mg. Preferably, the dose (preferably, aunit dose) of the glucokinase activator is about 5 mg, about 10 mg,about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, or any rangetherebetween. More preferably, the dose (preferably, a unit dose) of theglucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof) is about 25 mg,about 50 mg, about 75 mg, or about 100 mg. Preferably, in theabove-mentioned pharmaceutical combination, pharmaceutical composition,or pharmaceutical formulation (preferably, a fixed dose combinationformulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation) of the glucokinase activator(HMS5552 or an isotope labeled analogue or a pharmaceutically acceptablesalt thereof) and glimepiride, the dose (preferably, a unit dose) ofglimepiride is about 1 mg to about 4 mg. Preferably, the dose(preferably, a unit dose) of glimepiride is about 1 mg, about 2 mg, orabout 4 mg. Preferably, in the above-mentioned pharmaceuticalcombination, pharmaceutical composition, or pharmaceutical formulation(preferably, a fixed dose combination formulation), HMS5552 is presentin the form of a solid dispersion.

In the pharmaceutical combination, pharmaceutical composition, or fixeddose combination formulation of the present disclosure, the specificembodiments of the doses (preferably, unit doses) of HMS5552 (or anisotope labeled analogue or a pharmaceutically acceptable salt thereof)and glimepiride are as follows:

(1) about 25 mg of HMS5552 and about 1 mg of glimepiride;(2) about 50 mg of HMS5552 and about 1 mg of glimepiride;(3) about 75 mg of HMS5552 and about 1 mg of glimepiride;(4) about 100 mg of HMS5552 and about 1 mg of glimepiride;(5) about 25 mg of HMS5552 and about 2 mg of glimepiride;(6) about 50 mg of HMS5552 and about 2 mg of glimepiride;(7) about 75 mg of HMS5552 and about 2 mg of glimepiride; and(8) about 100 mg of HMS5552 and about 2 mg of glimepiride;preferably, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), HMS5552 is present in the form of asolid dispersion.

In one embodiment, the preferable dosage form of the pharmaceuticalcombination, pharmaceutical composition, or pharmaceutical formulation(preferably, a fixed dose combination formulation) of the presentdisclosure is a tablet.

In one embodiment, the above-mentioned tablet is a fixed dosecombination tablet of the glucokinase activator (HMS5552 or an isotopelabeled analogue or a pharmaceutically acceptable salt thereof) andglimepiride.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 25 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg glimepiride) comprisesthe components with the following amounts (by weight): about 25 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 1 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 50 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg glimepiride) contains thecomponents with the following amounts (by weight): about 50 mg of theglucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 1 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 75 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg glimepiride) comprisesthe components with the following amounts (by weight): about 75 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 1 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 100 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg glimepiride) comprisesthe components with the following amounts (by weight): about 100 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 1 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 25 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg glimepiride) comprisesthe components with the following amounts (by weight): about 25 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 50 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg glimepiride) comprisesthe components with the following amounts (by weight): about 50 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 75 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg glimepiride) comprisesthe components with the following amounts (by weight): about 75 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 100 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg glimepiride) comprisesthe components with the following amounts (by weight): about 100 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofglimepiride; about 0-75% of optional filler(s); about 2-8% of binder(s);about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about0-0.5% of glidant(s) and about 0-5% of coating agent(s); preferably, theabove-mentioned glucokinase activator is in the form of a soliddispersion as described above, or preferably the solid dispersioncontains a glucokinase activator and a polymer carrier, or preferablycontains about 1:1 of the glucokinase activator and Eudragit L100.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), the second active ingredient isrepaglinide. The above-mentioned pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulation of theglucokinase activator (HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof) and repaglinide contains (byweight): about 1 to 99.5% of the glucokinase activator (preferably,HMS5552 or an isotope labeled analogue or a pharmaceutically acceptablesalt thereof); about 0.05 to 8% of repaglinide; about 0 to 90% offiller(s); about 1 to 25% of binder(s); about 0-15% of disintegrant(s);about 0.1-10% of lubricant(s); about 0-3% of glidant(s); and about 0-5%of coating agent(s). The pharmaceutical composition or pharmaceuticalformulation (preferably, a fixed dose combination formulation) isprepared by a wet granulation method or a dry granulation method,preferably by a wet granulation method.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation) of the glucokinase activator(HMS5552 or an isotope labeled analogue or a pharmaceutically acceptablesalt thereof) and repaglinide, the dose (preferably, a unit dose) of theglucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof) is about 1 mg to200 mg. The alternative dose (preferably, a unit dose) of theglucokinase activator is about 5 mg to 100 mg. Preferably, the dose(preferably, a unit dose) of the glucokinase activator is about 5 mg,about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about50 mg, about 60 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg,or any range therebetween. More preferably, the dose (preferably, a unitdose) of the glucokinase activator (preferably, HMS5552 or an isotopelabeled analogue or a pharmaceutically acceptable salt thereof) is about25 mg, about 50 mg, about 75 mg, or about 100 mg. Preferably, in theabove-mentioned pharmaceutical combination, pharmaceutical composition,or pharmaceutical formulation (preferably, a fixed dose combinationformulation), HMS5552 is present in the form of a solid dispersion.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation) of the glucokinase activator(HMS5552 or an isotope labeled analogue or a pharmaceutically acceptablesalt thereof) and repaglinide, the dose (preferably, a unit dose) ofrepaglinide is about 0.5 mg to about 2 mg. Preferably, the dose(preferably, a unit dose) of repaglinide is about 0.5 mg, about 1 mg orabout 2 mg. Preferably, in the above-mentioned pharmaceuticalcombination, pharmaceutical composition, or pharmaceutical formulation(preferably, a fixed dose combination formulation), HMS5552 is presentin the form of a solid dispersion.

In the pharmaceutical combination, pharmaceutical composition, or fixeddose combination formulation composition of the present disclosure, thespecific embodiments of the doses (preferably, unit doses) of HMS5552and repaglinide are as follows:

(1) about 25 mg of HMS5552 and about 1 mg of repaglinide;(2) about 50 mg of HMS5552 and about 1 mg of repaglinide;(3) about 75 mg of HMS5552 and about 1 mg of repaglinide;(4) about 100 mg of HMS5552 and about 1 mg of repaglinide;(5) about 25 mg of HMS5552 and about 2 mg of repaglinide;(6) about 50 mg of HMS5552 and about 2 mg of repaglinide;(7) about 75 mg of HMS5552 and about 2 mg of repaglinide; and(8) about 100 mg of HMS5552 and about 2 mg of repaglinide.Preferably, in the above-mentioned pharmaceutical combination,pharmaceutical composition, or pharmaceutical formulation (preferably, afixed dose combination formulation), HMS5552 is present in the form of asolid dispersion.

In one embodiment, the preferable dosage form of the pharmaceuticalcombination, pharmaceutical composition, or pharmaceutical formulation(preferably, a fixed dose combination formulation) of the presentdisclosure is a tablet.

In one embodiment, the above-mentioned tablet is a fixed dosecombination tablet of the glucokinase activator (HMS5552 or an isotopelabeled analogue or a pharmaceutically acceptable salt thereof) andrepaglinide.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 25 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg repaglinide) comprisesthe components with the following amounts (by weight): about 25 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 1 mg ofrepaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 50 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg repaglinide) comprisesthe components with the following amounts (by weight): about 50 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 1 mg ofrepaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 75 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg repaglinide) comprisesthe components with the following amounts (by weight): about 75 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 1 mg ofrepaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 100 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/1 mg repaglinide tablet)comprises the components with the following amounts (by weight): about100 mg of the glucokinase activator (preferably, HMS5552 or an isotopelabeled analogue or a pharmaceutically acceptable salt thereof); about 1mg of repaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 25 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg repaglinide) comprisesthe components with the following amounts (by weight): about 25 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofrepaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 50 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg repaglinide) comprisesthe components with the following amounts (by weight): about 50 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofrepaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 75 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg repaglinide) comprisesthe components with the following amounts (by weight): about 75 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofrepaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition, or pharmaceutical formulation (preferably, a fixed dosecombination tablet, which is a tablet of 100 mg glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof)/2 mg repaglinide) comprisesthe components with the following amounts (by weight): about 100 mg ofthe glucokinase activator (preferably, HMS5552 or an isotope labeledanalogue or a pharmaceutically acceptable salt thereof); about 2 mg ofrepaglinide; about 0-90% of optional filler(s); about 1-25% ofbinder(s); about 1-15% of disintegrant(s); about 0.5-3% of lubricant(s);about 0-0.5% of glidant(s) and about 0-5% of coating agent(s); whereinthe above-mentioned glucokinase activator is in the form of a soliddispersion as described above.

In one embodiment, the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation) further comprises other excipients,wherein the other excipients include but are not limited to one or amixture of diluents, flavoring agents (flavors), sweetening agents, andcoloring agents.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition or pharmaceutical formulation (preferably, a fixed dosecombination formulation) disclosed herein contains optionally one ormore fillers (diluents). Examples of fillers include, but are notlimited to, cellulose derivatives such as microcrystalline cellulose orlignocellulose (including microcrystalline cellulose and silicifiedmicrocrystalline cellulose), lactose, anhydrous lactose or lactosemonohydrate, sucrose, starch, pregelatinized starch, dextrose, mannitol(including mannitol Pearlitol SD 200), fructose, xylitol, sorbitol, cornstarch, modified corn starch, inorganic salts such as calcium carbonate,calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/glucosebinder, maltodextrin, compressible sugar and other known compatibilizersor fillers/or a mixture of two or more of them.

Examples of preferable fillers (diluents) include microcrystallinecellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose,mannitol, sorbitol, calcium dihydrogen phosphate (dihydrate), cornstarch, pregelatinized starch and powdered cellulose. Other preferablefillers (diluents) are microcrystalline cellulose and silicifiedmicrocrystalline cellulose. Microcrystalline cellulose can be obtainedfrom several suppliers, including Avicel PH 101, Avicel PH 102, AvicelPH 103, Avicel PH 105, and Avicel PH 200 manufactured by FMCCorporation.

In one embodiment, the pharmaceutical combination, pharmaceuticalcomposition or pharmaceutical formulation (preferably, a fixed dosecombination formulation) disclosed herein contains optionally one ormore binders. Examples include, but are not limited to,carboxymethylcellulose (including sodium carboxymethylcellulose),hydroxypropyl cellulose (including hydroxypropyl cellulose EXF), cornstarch, pregelatinized starch, modified corn starch, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) (includinghydroxypropylmethyl cellulose 2208), lactose, sucrose, gum arabic,ethylcellulose, cellulose acetate and wax binders such as carnauba wax,paraffin wax, cetyl wax, polyethylene or microcrystalline wax and otherconventional binder and/or a mixture of two or more of them. Further, inaddition to the above binders, binders suitable for use in the presentdisclosure include, but are not limited to, alginic acid,microcrystalline cellulose, dextrin, gelatin, amylopectin, liquidglucose, guar gum, methylcellulose, polyethylene oxide, povidone andsyrup, and the combination of them.

Preferable embodiments of the binder include hydroxypropyl cellulose(HPC), hydroxypropyl methyl cellulose (HMPC), polyvinylpyrrolidone(Povidone), hydroxyethyl cellulose, starch 1500 and Polyvidon. Otherpreferable binders are hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

In one embodiment, the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation) contains optionally one or moredisintegrants. Examples of disintegrants suitable for use in the presentdisclosure include, but are not limited to, croscarmellose sodium,crospovidone, lactose, sucrose, starch, potato starch, pregelatinizedstarch, corn starch, sodium carboxymethyl starch, sodium starchglycolate, microcrystalline cellulose, light silicic acid anhydride,low-substituted hydroxypropyl cellulose and other known disintegrants.

In one embodiment, the disintegrant is selected from one or more ofmodified starch, modified cellulose polymer or polycarboxylic acid,specifically selected from the group consisting of croscarmellosesodium, crospovidone, sodium starch glycolate, polacrilin potassium andCMC Calcium. In one embodiment, the disintegrant is crospovidone. Inanother embodiment, the disintegrant is sodium starch glycolate. Inanother embodiment, the disintegrant is croscarmellose sodium.Croscarmellose sodium NF type A is available in the market under thetrade name “Ac-di-sol”.

In one embodiment, the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation) contains one or more lubricants.Examples of lubricants suitable for use in the present disclosureinclude, but are not limited to, magnesium stearate, zinc stearate,calcium stearate, talc, carnauba wax, stearic acid, palmitic acid,sodium stearyl fumarate, sodium lauryl sulphate, glyceryl palmitatestearate, palmitic acid, myristic acid and hydrogenated vegetable oils(including hydrogenated castor oil) and fats and other known lubricantsand/or a mixture of two or more of them.

In one embodiment, embodiments of the lubricant include magnesiumstearate, calcium stearate, stearic acid, sodium stearyl fumarate,hydrogenated castor oil, and a mixture thereof. Another preferablelubricant is magnesium stearate, or sodium stearyl fumarate, or amixture thereof.

In one embodiment, the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation) contains one or more glidants and/oranti-adherents. Examples of glidants and/or anti-adherents suitable foruse in the present disclosure include, but are not limited to, silicondioxide, colloidal silicon dioxide, calcium phosphate, magnesiumsilicate, magnesium trisilicate, talc and other forms of silicon dioxidesuch as aggregated silicate and hydrated silica gel.

In one embodiment, embodiments of the glidant include colloidal silicondioxide, calcium phosphate, magnesium silicate, and talc, or a mixturethereof. The preferable glidant is colloidal silicon dioxide.

In one embodiment, the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation) may also optionally contain one ormore surfactants or wetting agents. The surfactant can be an anionic,cationic or neutral surfactant. The anionic surfactant includes sodiumdodecyl sulfate, sodium lauryl sulfonate, sodium oleyl sulfate, andsodium laurate mixed with stearate and talc. The cationic surfactantincludes benzalkonium chloride and alkyl trimethyl ammonium bromide. Theneutral surfactant includes glycerol monooleate, polyoxyethylenesorbitan fatty acid ester, polyvinyl alcohol and sorbitan ester.Embodiments of the wetting agent include poloxamer, polyoxyethylenealkyl ether, polyoxyethylene castor oil derivative, and polyoxyethylenestearate.

In one embodiment, the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation) may also optionally contain anantioxidant to render chemical stability. Examples of the antioxidantsuitable for use in the present disclosure include, but are not limitedto, tocopherol, ascorbic acid, gallic acid ester, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol,potassium metabisulfite, propionic acid, propyl gallate, sodiumascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite anda combination thereof.

In one embodiment, the antioxidant is selected from the group consistingof α-tocopherol, γ-tocopherol, δ-tocopherol, extracts from naturalsources enriched in tocopherol, L-ascorbic acid and sodium or calciumsalt thereof, ascorbyl palmitate, propyl gallate, octyl gallate, laurylgallate, butylated hydroxytoluene (BHT) and butylated hydroxyanisole(BHA). In one embodiment, the antioxidant is BHT or BHA.

In one embodiment, the preferable formulation of the above-mentionedfixed dose combination formulation is a tablet prepared by a compressionmethod. The tablet may be coated, and preferable examples of coatingsubstrates include sugar coating substrates, water-soluble film coatingsubstrates, enteric film coating substrates, and the like.

Sucrose is used as the sugar coating substrate. In addition, one or moreselected from talc powder, precipitated calcium carbonate, gelatin, gumarabic, amylopectin, carnauba wax, and the like can also be used incombination.

Examples of the water-soluble film coating substrate include cellulosicpolymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, andthe like; synthetic polymers such as polyvinyl acetaldiethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E(trade name)], polyvinylpyrrolidone, and the like.

Examples of the enteric film coating substrate include cellulosicpolymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethyl ethyl cellulose,cellulose acetate phthalate, and the like; acrylic polymer, such asmethacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acidcopolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymerS [Eudragit S (trade name)], and the like.

Preferable examples of coating additives include: plasticizers such aspolyvinyl alcohol (PVA), polyethylene glycol (PEG), propylene glycol,triethyl citrate, castor oil, polysorbate, and the like, or a mixture oftwo or more of them; opacifiers such as titanium dioxide and the like;coloring agents, dyes and lakes such as iron oxide red (ferric oxide),iron oxide yellow, and the like; and glidants such as talc and the like.

In one embodiment, the tablet may be coated with, for example, a mixtureof hydroxypropylcellulose and hydroxypropylmethylcellulose, wherein themixture contains titanium dioxide and/or other coloring agents, such asiron oxide, dyes and lakes; a mixture of polyvinyl alcohol (PVA) andpolyethylene glycol (PEG); or any other suitable immediate-releasecoating agent. The coating provides taste masking and additionalstability to the final tablet. The commercially available coatingmaterial is Opadry® such as Opadry 03K12429 which is a pre-formulatedpowder mixture provided by Colorcon.

In one embodiment, in the above-mentioned pharmaceutical combination,pharmaceutical composition or pharmaceutical formulation (preferably, afixed dose combination formulation), sweetening agents and/or flavoringagents may also be added as needed.

In one embodiment, the above-mentioned binder is polyvinylpyrrolidone,hydroxypropyl cellulose or hydroxypropyl methyl cellulose, theabove-mentioned filler is microcrystalline cellulose, silicifiedmicrocrystalline cellulose, lactose, calcium dihydrogen phosphate,mannitol, corn starch or pregelatinized starch, the above-mentioneddisintegrant is croscarmellose sodium, crospovidone or sodium starchglycolate, the above-mentioned lubricant is magnesium stearate or sodiumstearyl fumarate, and the above-mentioned glidant is colloidal silicondioxide.

In one embodiment, the above-mentioned binder is hydroxypropylcellulose, the above-mentioned filler is microcrystalline cellulose,silicified microcrystalline cellulose or lactose, the above-mentioneddisintegrant is croscarmellose sodium, crospovidone or sodium starchglycolate, the above-mentioned lubricant is magnesium stearate or sodiumstearyl fumarate, and the above-mentioned glidant is colloidal silicondioxide.

In one embodiment, the above-mentioned binder is polyvinylpyrrolidone,the above-mentioned filler is microcrystalline cellulose or silicifiedmicrocrystalline cellulose, the above-mentioned disintegrant iscroscarmellose sodium or crospovidone, the above-mentioned lubricant ismagnesium stearate or sodium stearyl fumarate, and the above-mentionedglidant is colloidal silicon dioxide.

In one embodiment, the above-mentioned binder is hydroxypropyl methylcellulose, the above-mentioned filler is microcrystalline cellulose,silicified microcrystalline cellulose or lactose, the above-mentioneddisintegrant is croscarmellose sodium, crospovidone or sodium starchglycolate, the above-mentioned lubricant is magnesium stearate or sodiumstearyl fumarate, and the above-mentioned glidant is colloidal silicondioxide.

In one embodiment, the above-mentioned binder is hydroxypropylcellulose, the above-mentioned filler is microcrystalline cellulose,silicified microcrystalline cellulose or lactose, the above-mentioneddisintegrant is croscarmellose sodium, and the above-mentioned lubricantis magnesium stearate or sodium stearyl fumarate.

In one embodiment, the above-mentioned binder is polyvinylpyrrolidone,the above-mentioned lubricant is magnesium stearate, and theabove-mentioned glidant is colloidal silicon dioxide.

Preparation Method

In one embodiment, the pharmaceutical composition or fixed dosecombination formulation disclosed herein is prepared by wet granulation(high shear and/or fluidized bed). The granulation is a method in whichbinder(s) is added into a solvent to prepare a binder solution, and thenadded or directly added into a granulator to prepare wet granules. Thewet granulation method includes the steps of:

(1) adding an active pharmaceutical ingredient glucokinase activator(preferably, HMS5552) and a partner drug (preferably, glimepiride orrepaglinide) into a granulator;(2) adding optional filler(s) (e.g., microcrystalline cellulose,silicified microcrystalline cellulose, or lactose) into the mixtureobtained in step (1);(3) adding optional disintegrant(s) (e.g., croscarmellose sodium,crospovidone, or sodium starch glycolate) into the mixture obtained instep (1) or (2);(4) for high-shear granulation, adding binder(s) (e.g., hydroxypropylcellulose, polyvinylpyrrolidone or hydroxypropyl methyl cellulose) intopure water to prepare a binder solution, and then adding it into agranulator for granulation with stirring. For fluidized bed granulation,two active pharmaceutical ingredients are added into a fluidized bed,and a binder solution that is an aqueous solution prepared frombinder(s) and pure water is sprayed into the fluidized bed by compressedair;(5) sizing the obtained wet granules in a suitable mill to obtain wetgranules of suitable size;(6) for granules prepared by high-shear granulation, drying with a trayin an oven or drying in a fluidized bed dryer; and for granules obtainedby granulating in a fluidized bed, drying in a fluidized bed;(7) sizing the granules on a suitable grinder to obtain dry granules ofsuitable size;(8) in a suitable mixer, adding optional filler(s) (diluent(s), such asmicrocrystalline cellulose) and optional disintegrant(s) (e.g.,croscarmellose sodium), and mixing with the dry granules;(9) adding lubricant(s) (e.g., magnesium stearate and sodium stearylfumarate) into the mixture in step (8);(10) adding optional glidant(s) (e.g., colloidal silicon dioxide) intothe mixture in step (9);(11) filling the mixture of lubricated granules in step (9) or (10) intovials, pouches or capsules, or compressing it into a tablet with adesired shape; and(12) optionally, film-coating the obtained tablets.

In another embodiment, the pharmaceutical composition disclosed hereinis prepared by wet granulation (high shear and/or fluidized bed). Thegranulation is a method in which binder(s) and a second activeingredient are added into a solvent to prepare a binder solution (orsuspension), and then added into a granulator to prepare wet granules.The wet granulation method includes the steps of:

(1) adding the active pharmaceutical ingredient glucokinase activator(preferably, HMS5552) into a granulator;(2) adding optional filler(s) (e.g., microcrystalline cellulose,silicified microcrystalline cellulose, or lactose) into the mixture instep (1);(3) adding optional disintegrant(s) (e.g., croscarmellose sodium,crospovidone, or sodium starch glycolate) into the mixture obtained instep (1) or (2);(4) for high-shear granulation, adding binder(s) (e.g., hydroxypropylcellulose, polyvinylpyrrolidone or hydroxypropyl methyl cellulose) intoa solvent for uniform dispersion or dissolution, and then adding thesecond active ingredient (preferably, glimepiride or repaglinide) in aformulated amount for dispersion or dissolution, so as to form a uniformbinder system. The system is added into a granulator for granulationwith stirring. For fluidized bed granulation, an active pharmaceuticalingredient such as HMS5552 is added into a fluidized bed, and a bindersystem that is a solution or suspension prepared by binder(s) and purewater or an organic solvent (e.g., ethanol) is sprayed into thefluidized bed by compressed air;(5) sizing the obtained wet granules in a suitable mill to obtain wetgranules of suitable size;(6) for granules prepared by high-shear granulation, drying with a trayin an oven or drying in a fluidized bed dryer; and for granules obtainedby granulating in a fluidized bed, drying in a fluidized bed;(7) sizing the granules on a suitable grinder to obtain dry granules ofsuitable size;(8) in a suitable mixer, adding optional filler(s) (diluent, such asmicrocrystalline cellulose) and optional disintegrant(s) (e.g.,croscarmellose sodium), and mixing with the dry granules;(9) adding lubricant(s) (e.g., magnesium stearate and sodium stearylfumarate) into the mixture in step (8);(10) optionally, adding optional glidant(s) (e.g., colloidal silicondioxide) into the mixture in step (9);(11) filling the mixture of lubricated granules in (9) or (10) intovials, pouches or capsules, or compressing it into a tablet with adesired shape; and(12) optionally, film-coating the obtained tablets.

The dry processing (direct compression or dry granulation) methodincludes the steps of:

(1) adding the active pharmaceutical ingredient glucokinase activator(preferably, HMS5552) and the partner drug (preferably, glimepiride orrepaglinide) into a mixing tank;(2) adding optional filler(s) (e.g., microcrystalline cellulose,silicified microcrystalline cellulose, or lactose) into the mixture instep (1);(3) adding optional binder(s) (e.g., hydroxypropyl cellulose,polyvinylpyrrolidone or hydroxypropyl methyl cellulose) into the mixtureobtained in step (1) or (2);(4) adding lubricant(s) or glidant(s) into the mixture in step (3), andmixing;(5) filling the mixture in step (4) into vials, pouches or capsules,compressing the mixture in step (4) into a tablet with a desired shape,or processing the mixture in step (4) by a roller compressor;(6) mixing the mixture in step (3) in advance, and then rolled with aroller if processing the mixture in step (4) by a roller compressor; ifnecessary, sizing the granules on a suitable grinder to obtain granulesof the required size;(7) in a suitable mixer, adding optional diluent(s) to the granulesobtained in step (6) to improve the compression performance;(8) adding optional disintegrant(s) (e.g., croscarmellose sodium,crospovidone, or sodium starch glycolate) into the mixture in step (7);(9) adding optional lubricant(s) or glidant(s) into the mixture in step(8);(10) filling the mixture of lubricated granules in step (9) or (10) intovials, pouches or capsules, or compressing it into a tablet with adesired shape; and(11) optionally, film-coating the tablets obtained in step (5) or step(10).

In one embodiment disclosed herein, the glucokinase activator in thepharmaceutical combination, pharmaceutical composition or fixed dosecombination formulation disclosed herein is in the form of a soliddispersion, which can be prepared by a method selected from the groupconsisting of spray drying method, fluidized bed drying method, solventmethod, melt extrusion method and the like.

One embodiment disclosed herein is a method of preparing a soliddispersion of a glucokinase activator by a spray drying method, whichincludes the steps of:

(1) formulating a spray drying solution, including dissolving a polymercarrier and a glucokinase activator (preferably, HMS5552) in a solvent;(2) spray drying, including controlling the temperature of the inletair, the amount of the inlet air, the flow rate and pressure of theatomized airflow, the spraying speed of the solution, and the like.

In the embodiment disclosed herein, the solvent used in the preparationof the solid dispersion of the glucokinase activator includes but is notlimited to alkanols, esters, nitriles, cycloalkanes, aromatichydrocarbons, ketones and the like. Specifically, the solvent isselected from the group consisting of anhydrous ethanol, methanol,isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane,benzene and toluene. The solvent can be a single solvent, a mixedsolvent, or a mixture of an organic solvent and water.

Methods and Uses for Treating and/or Preventing Diseases

Another embodiment disclosed herein relates to a method or use of acomposition or formulation (preferably, a fixed dose combinationpharmaceutical composition or a fixed dose combination formulation)comprising a glucokinase activator disclosed herein for the treatmentand/or prevention of the following diseases and medical disorders,especially one or more diseases selected from the group consisting oftype I diabetes, type II diabetes, impaired glucose tolerance, impairedfasting blood glucose, and hyperglycemia, including administering to asubject a therapeutically effective amount of the composition orpreparation (preferably, a fixed dose combination pharmaceuticalcomposition or a fixed dose combination formulation) disclosed herein:

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder selected from the group consisting of type 1        diabetes mellitus, type 2 diabetes mellitus, impaired glucose        tolerance, impaired fasting blood glucose, hyperglycemia,        postprandial hyperglycemia, overweight, obesity and metabolic        syndrome; or    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c; or    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance, insulin resistance and/or from        metabolic syndrome to type 2 diabetes mellitus; or    -   preventing, slowing the progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus such as cataracts and micro-        and macrovascular diseases, such as nephropathy, retinopathy,        neuropathy, learning and memory dysfunction, neurodegenerative        or cognitive disorders, cardio- or cerebrovascular diseases,        tissue ischaemia, diabetic foot or ulcus, arteriosclerosis,        hypertension, endothelial dysfunction, myocardial infarction,        accute coronary syndrome, unstable angina pectoris, stable        angina pectoris, stroke, peripheral arterial occlusive disease,        cardiomyopathy, heart failure, heart rhythm disorders and        vascular restenosis; or    -   reducing body weight and/or body fat or preventing an increase        in body weight and/or body fat or facilitating a reduction in        body weight and/or body fat; or    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring or        protecting the functionality of pancreatic beta cells and/or        restoring the functionality of pancreatic insulin secretion; or    -   for preventing, slowing, delaying or treating diseases or        conditions attributed to an abnormal accumulation of liver or        ectopic fat; or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance; or    -   for preventing, slowing progression of, delaying, or treating        new onset diabetes after transplantation (NODAT) and/or        post-transplant metabolic syndrome (PTMS); or    -   for preventing, delaying, or reducing NODAT and/or PTMS        associated complications including micro- and macrovascular        diseases and events, graft rejection, infection, and death; or    -   for treating hyperuricemia and hyperuricemia associated        conditions; or    -   for preventing, slowing, delaying or treating maturity-onset        diabetes of the young (MODY), and diseases associated with islet        dysfunction.

The present disclosure also provides a method for the treatment of typeII diabetes by orally administering a therapeutically effective amountof a pharmaceutical composition or formulation (preferably, a fixed dosecombination pharmaceutical composition or a fixed dose combinationformulation) comprising a glucokinase activator and a partner drugdisclosed herein to a subject in need of the treatment. In oneembodiment, the subject in need of the treatment is a human. In anotherembodiment, the pharmaceutical composition is in the form of a tablet.The composition or formulation (preferably, a fixed dose combinationpharmaceutical composition or a fixed dose combination formulation)comprising a glucokinase activator disclosed herein can be administeredonce a day (QD), twice a day (BID) or three times a day (TID).

Specifically, the present disclosure relates to the following specificembodiments.Embodiment I-Glucokinase Activator+K-ATP Channel Blocker (e.g.Glimepiride)

Solution 1. A pharmaceutical combination, a pharmaceutical composition,or a fixed dose combination formulation, comprising:

(a) a glucokinase activator, which is a compound represented by thefollowing formulae, or a pharmaceutically acceptable salt, an isotopelabeled analogue, a crystalline form, a hydrate, a solvate, or adiastereomeric or enantiomeric form thereof,

(b) a K-ATP channel blocker; and(c) one or more excipients;wherein the above-mentioned drugs (a) and (b) are used simultaneously,separately or sequentially.

Solution 2. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 1, wherein the weightratio of the glucokinase activator to the K-ATP channel blocker is about400:1 to 10:1, preferably about 100:1 to 25:2, or more preferably about25:2, about 25:1, about 50:1, about 75:2, about 75:1, or about 100:1.

Solution 3. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 1 or 2, wherein theglucokinase activator is about 1-99% by weight; and the K-ATP channelblocker is about 0.1-15% by weight.

Solution 4. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-3,wherein the glucokinase activator is the compound HMS5552 represented bythe following formula, or a pharmaceutically acceptable salt, an isotopelabeled analogue, a crystalline form, a hydrate, a solvate, or adiastereomeric or enantiomeric form thereof,

Solution 5. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-4,wherein the glucokinase activator is in the form of a solid dispersion.

Solution 6. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 5, wherein theglucokinase activator is in the form of a solid dispersion containing apolymer carrier, and the polymer carrier is a methacrylic acid copolymerof type A (an anionic copolymer of methacrylic acid and methylmethacrylate (1:1)), preferably Eudragit, or more preferably EudragitL100.

Solution 7. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 6, wherein the weightratio of the glucokinase activator to the polymer carrier is about 1:10to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6to 6:5, or more preferably about 1:1, about 2:3, about 3:4, about 4:5 orabout 5:6 or any range therebetween.

Solution 8. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-7,wherein the K-ATP channel blocker is selected from the group consistingof sulfonylurea secretagogues including glibenclamide, glipizide,gliclazide, gliquidone and glimepiride, and a pharmaceuticallyacceptable salt thereof; or selected from the group consisting ofnon-sulfonylurea insulin secretagogues including repaglinide andnateglinide, and a pharmaceutically acceptable salt thereof.

Solution 9. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-8,wherein the glucokinase activator is present in a dose (preferably, aunit dose) ranging from about 1 mg to about 200 mg, or preferably about25 mg to about 100 mg, preferably, wherein the dose (preferably, a unitdose) of the glucokinase activator is about 25 mg, about 50 mg, about 75mg, or about 100 mg.

Solution 10. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-9,wherein the K-ATP channel blocker is present in a dose (preferably, aunit dose) ranging from about 0.1 mg to about 10 mg, or preferably about1 mg to about 5 mg, preferably, wherein the dose (preferably, a unitdose) of the K-ATP channel blocker is about 0.1 mg, about 0.2 mg, about0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 4 mg or about 5 mg,or still preferably about 1 mg or about 2 mg; and preferably, the K-ATPchannel blocker is glimepiride or repaglinide.

Solution 11. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-10,wherein the one or more excipients are selected from the groupconsisting of binders, fillers, disintegrants, lubricants, glidants,surfactants, wetting agents, antioxidants, flavoring agents, sweeteningagents, coloring agents and coating agents.

Solution 12. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-11,which is a tablet.

Solution 13. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 12, which is a coatedtablet.

Solution 14. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 13, wherein the coatedtablet is a film-coated tablet, and the film-coating agent comprises:

film-coating substrate(s), such as hypromellose, hydroxypropyl methylcellulose, or a mixture thereof;optional plasticizer(s), such as polyvinyl alcohol, polyethylene glycol,propylene glycol, polysorbate, or a mixture thereof;optional coloring agent(s), such as iron oxide red, iron oxide yellow,or a mixture thereof; optional opacifier(s), such as titanium dioxide,andoptional glidant(s).

Solution 15. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 14, wherein the coatedtablet is a film-coated tablet, and the film-coating agent is Opadry.

Solution 16. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-15,comprising (by weight): about 1-99% of the glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof), preferably HMS5552,preferably a solid dispersion of HMS5552, preferably a solid dispersioncontaining HMS5552 and a polymer carrier, or preferably a soliddispersion containing about 1:1 of HMS5552 and Eudragit L100;

about 0.1-15% of glimepiride;about 0-85% of filler(s);about 1-25% of binder(s);about 0-15% of disintegrant(s);about 0.1-10% of lubricant(s);about 0-3% of glidant(s); andabout 0-3% of coating agent(s).

Solution 17. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 16, comprising (byweight):

about 1 to 50% of the glucokinase activator (preferably, HMS5552 or anisotope labeled analogue or a pharmaceutically acceptable salt thereof),preferably HMS5552, preferably a solid dispersion of HMS5552, preferablya solid dispersion containing HMS5552 and a polymer carrier, orpreferably a solid dispersion containing about 1:1 of HMS5552 andEudragit L100;about 0.1-8% of glimepiride;about 0-90% of filler(s);about 1-10% of binder(s);about 1-10% of disintegrant(s);about 0.1-5% of lubricant(s);about 0-3% of glidant(s); andabout 0-3% of coating agent(s).

Solution 18. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 16, wherein the doses(preferably, unit doses) of the active ingredients are (by weight):

about 25 mg, about 50 mg, about 75 mg or about 100 mg of the glucokinaseactivator, or preferably HMS5552;about 1 mg, about 2 mg or about 4 mg of glimepiride;about 0-85% of filler(s);about 1-25% of binder(s);about 0-15% of disintegrant(s);about 0.1-10% of lubricant(s);about 0-3% of glidant(s); andabout 0-3% of coating agent(s).

Solution 19. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 50 mg HMS5552/1 mg glimepiride) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 50 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 1 mg of glimepiride;    -   about 0-80% of filler(s);    -   about 2-8% of binder(s);    -   about 1-5% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 20. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 75 mg HMS5552/1 mg glimepiride) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 75 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 1 mg of glimepiride;    -   about 0-80% of filler(s);    -   about 2-8% of binder(s);    -   about 1-5% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 21. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 100 mg HMS5552/1 mg glimepiride)of solution 18, comprising the components with the following amounts (byweight):

-   -   about 100 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 1 mg of glimepiride;    -   about 0-80% of filler(s);    -   about 2-8% of binder(s);    -   about 1-5% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 22. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 25 mg HMS5552/2 mg glimepiride) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 25 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 2 mg of glimepiride;    -   about 0-80% of filler(s);    -   about 2-8% of binder(s);    -   about 1-5% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 23. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 50 mg HMS5552/2 mg glimepiride) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 50 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 2 mg of glimepiride;    -   about 0-80% of filler(s);    -   about 2-8% of binder(s);    -   about 1-5% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 24. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 75 mg HMS5552/2 mg glimepiride) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 75 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 2 mg of glimepiride;    -   about 0-80% of filler(s);    -   about 2-8% of binder(s);    -   about 1-5% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 25. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about100 mg of the solid dispersion, about 1.00 mg of glimepiride, about129.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropylcellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg ofsodium dodecyl sulfate, about 2.50 mg of magnesium stearate and about7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 50 mg of HMS5552.

Solution 26. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about150 mg of the solid dispersion, about 1.00 mg of glimepiride, about79.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropylcellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg ofsodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 75 mg of HMS5552.

Solution 27. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about200 mg of the solid dispersion, about 1.00 mg of glimepiride, about29.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropylcellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg ofsodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 100 mg of HMS5552.

Solution 28. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about100 mg of the solid dispersion, about 2.00 mg of glimepiride, about128.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropylcellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg ofsodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 50 mg of HMS5552.

Solution 29. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about150 mg of the solid dispersion, about 2.00 mg of glimepiride, about78.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropylcellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg ofsodium dodecyl sulfate, about 2.50 mg of magnesium stearate and about7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 75 mg of HMS5552.

Solution 30. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about50 mg of the solid dispersion, about 2.00 mg of glimepiride, about136.00 microcrystalline cellulose, and about 4.00 mg of hydroxypropylcellulose, about 4.00 croscarmellose sodium, about 2.00 mg of sodiumdodecyl sulfate, about 2.00 mg of magnesium stearate and about 6.00 mgof Opadry, wherein the solid dispersion contains about 1:1 of HMS5552and Eudragit L100, and contains about 25 mg of HMS5552.

Solution 31. A method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulation of anyone of solutions 1-30, comprising incorporating the active ingredientsinto one or more excipients for granulation, preferably further fillingthe obtained granule mixture into a vial, a sachet or a capsule, orcompressing it into a tablet with a desired shape; and more preferably,further coating the obtained tablet.

Solution 32. The method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulationaccording to solution 31, wherein the preparation is carried out by wetgranulation (high shear and/or fluidized bed), or by dry processing(direct compression or dry granulation).

Solution 33. The method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulationaccording to any one of solutions 30-31, wherein the glucokinaseactivator is prepared in the form of a solid dispersion.

Solution 34. The method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulationaccording to any one of solutions 30-32, wherein the glucokinaseactivator and the second or more active ingredients can also be preparedtogether in the form of a combination solid dispersion (that is, a soliddispersion comprising two or more active ingredients).

Solution 35. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-30,which is used to prevent, slow the progression of, delay, or treat oneor more metabolic disorders selected from the group consisting of: typeI diabetes, type II diabetes, maturity-onset diabetes of the young(MODY), impaired glucose tolerance, impaired fasting blood glucose,hyperglycemia, postprandial hyperglycemia, overweight, obesity,hypertension, insulin resistance, diseases associated with isletdysfunction and/or metabolic syndrome; or improve blood glucose controland/or reduce fasting plasma glucose, postprandial plasma glucose and/orglycosylated hemoglobin HbA1c; or prevent, slow, delay, or reversecomplications of diabetes mellitus.

Solution 36. A method for preventing, slowing the progression of,delaying, or treating one or more metabolic disorders selected from thegroup consisting of: type I diabetes, type II diabetes, maturity-onsetdiabetes of the young (MODY), impaired glucose tolerance, impairedfasting blood glucose, hyperglycemia, postprandial hyperglycemia,overweight, obesity, hypertension, insulin resistance, diseasesassociated with islet dysfunction and/or metabolic syndrome; orimproving blood glucose control and/or reducing fasting plasma glucose,postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; orpreventing, slowing, delaying, or reversing complications of diabetesmellitus, comprising administering to a subject a therapeuticallyeffective amount of the pharmaceutical combination, pharmaceuticalcomposition or fixed dose combination formulation of any one ofsolutions 1-30.

Solution 37. Use of the pharmaceutical combination, pharmaceuticalcomposition or fixed dose combination formulation of any one ofsolutions 1-30 in the manufacture of a medicament for preventing,slowing the progression of, delaying, or treating one or more metabolicdisorders selected from the group consisting of: type I diabetes, typeII diabetes, maturity-onset diabetes of the young (MODY), impairedglucose tolerance, impaired fasting blood glucose, hyperglycemia,postprandial hyperglycemia, overweight, obesity, hypertension, insulinresistance, diseases associated with islet dysfunction and/or metabolicsyndrome; or improving blood glucose control and/or reducing fastingplasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin HbA1c.

Embodiment II-Glucokinase Activator+K-ATP Channel Blocker (e.g.Repaglinide)

Solution 1. A pharmaceutical combination, a pharmaceutical composition,or a fixed dose combination formulation, comprising:

(a) a glucokinase activator, which is a compound represented by thefollowing formulae, or a pharmaceutically acceptable salt, an isotopelabeled analogue, a crystalline form, a hydrate, a solvate, or adiastereomeric or enantiomeric form thereof,

(b) a K-ATP channel blocker; and(c) one or more excipients;wherein the above-mentioned drugs (a) and (b) are used simultaneously,separately or sequentially.

Solution 2. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 1, wherein the weightratio of the glucokinase activator to the K-ATP channel blocker is about400:1 to 10:1, preferably about 100:1 to 25:2, or more preferably about25:2, about 25:1, about 50:1, about 75:2, about 75:1, or about 100:1.

Solution 3. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 1 or 2, wherein theglucokinase activator is about 1-99% by weight; and the K-ATP channelblocker is about 0.1-8% by weight.

Solution 4. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-3,wherein the glucokinase activator is the compound HMS5552 represented bythe following formula, or a pharmaceutically acceptable salt, an isotopelabeled analogue, a crystalline form, a hydrate, a solvate, or adiastereomeric or enantiomeric form thereof,

Solution 5. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-4,wherein the glucokinase activator is in the form of a solid dispersion.

Solution 6. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 5, wherein theglucokinase activator is in the form of a solid dispersion containing apolymer carrier, and the polymer carrier is a methacrylic acid copolymerof type A (an anionic copolymer of methacrylic acid and methylmethacrylate (1:1)), preferably Eudragit, or more preferably EudragitL100.

Solution 7. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 6, wherein the weightratio of the glucokinase activator to the polymer carrier is about 1:10to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6to 6:5, or more preferably about 1:1, about 2:3, about 3:4, about 4:5 orabout 5:6 or any range therebetween.

Solution 8. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-7,wherein the K-ATP channel blocker is selected from the group consistingof sulfonylurea secretagogues including glibenclamide, glipizide,gliclazide, gliquidone and glimepiride, and a pharmaceuticallyacceptable salt thereof; or selected from the group consisting ofnon-sulfonylurea insulin secretagogues including repaglinide andnateglinide, and a pharmaceutically acceptable salt thereof.

Solution 9. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-8,wherein the glucokinase activator is present in a dose (preferably, aunit dose) ranging from about 1 mg to about 200 mg, or preferably about25 mg to about 100 mg, preferably, wherein the dose (preferably, a unitdose) of the glucokinase activator is about 25 mg, about 50 mg, about 75mg, or about 100 mg.

Solution 10. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-9,wherein the K-ATP channel blocker is present in a dose (preferably, aunit dose) ranging from about 0.1 mg to about 10 mg, or preferably about1 mg to about 5 mg, preferably, wherein the dose (preferably, a unitdose) of the K-ATP channel blocker is about 0.1 mg, about 0.2 mg, about0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 4 mg or about 5 mg,or still preferably about 1 mg or about 2 mg; and preferably, the K-ATPchannel blocker is glimepiride or repaglinide.

Solution 11. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-9,wherein the one or more excipients are selected from the groupconsisting of binders, fillers, disintegrants, lubricants, glidants,surfactants, wetting agents, antioxidants, flavoring agents, sweeteningagents, coloring agents and coating agents.

Solution 12. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-11,which is a tablet.

Solution 13. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 12, which is a coatedtablet.

Solution 14. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 13, wherein the coatedtablet is a film-coated tablet, and the film-coating agent comprises:

film-coating substrate(s), such as hypromellose, hydroxypropyl methylcellulose, or a mixture thereof;optional plasticizer(s), such as polyvinyl alcohol, polyethylene glycol,propylene glycol, polysorbate, or a mixture thereof;optional coloring agent(s), such as iron oxide red, iron oxide yellow,or a mixture thereof; optional opacifier(s), such as titanium dioxide,andoptional glidant(s).

Solution 15. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 14, wherein the coatedtablet is a film-coated tablet, and the film-coating agent is Opadry.

Solution 16. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-15,comprising (by weight): about 1-99% of the glucokinase activator(preferably, HMS5552 or an isotope labeled analogue or apharmaceutically acceptable salt thereof), preferably HMS5552,preferably a solid dispersion of HMS5552, preferably a solid dispersioncontaining HMS5552 and a polymer carrier, or preferably a soliddispersion containing about 1:1 of HMS5552 and Eudragit L100;

about 0.1-8% of repaglinide;about 0-90% of filler(s);about 1-25% of binder(s);about 0-15% of disintegrant(s);about 0.1-10% of lubricant(s);about 0-3% of glidant(s); andabout 0-5% of coating agent(s).

Solution 17. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 15, comprising (byweight):

about 1 to 50% of the glucokinase activator (preferably, HMS5552 or anisotope labeled analogue or a pharmaceutically acceptable salt thereof),preferably HMS5552, preferably a solid dispersion of HMS5552, preferablya solid dispersion containing HMS5552 and a polymer carrier, orpreferably a solid dispersion containing about 1:1 of HMS5552 andEudragit L100;about 0.1-5% of repaglinide;about 0-90% of filler(s);about 1-10% of binder(s);about 1-10% of disintegrant(s);about 0.1-5% of lubricant(s);about 0-3% of glidant(s); andabout 0-5% of coating agent(s).

Solution 18. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 15, wherein the doses(preferably, unit doses) of the active ingredients are (by weight):

about 25 mg, about 50 mg, about 75 mg or about 100 mg of the glucokinaseactivator, or preferably HMS5552;about 0.5 mg, about 1 mg or about 2 mg of repaglinide;about 0-90% of filler(s);about 1-25% of binder(s);about 0-15% of disintegrant(s);about 0.1-10% of lubricant(s);about 0-3% of glidant(s); andabout 0-5% of coating agent(s).

Solution 19. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 75 mg HMS5552/1 mg repaglinide) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 75 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 1 mg of repaglinide;    -   about 0-95% of filler(s);    -   about 1-25% of binder(s);    -   about 1-8% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 20. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 50 mg HMS5552/2 mg repaglinide) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 50 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 2 mg of repaglinide;    -   about 0-95% of filler(s);    -   about 1-25% of binder(s);    -   about 1-8% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 21. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation (the fixed dose combinationformulation is preferably a tablet of 25 mg HMS5552/2 mg repaglinide) ofsolution 18, comprising the components with the following amounts (byweight):

-   -   about 25 mg of HMS5552, preferably a solid dispersion of        HMS5552, preferably a solid dispersion containing HMS5552 and a        polymer carrier, or preferably a solid dispersion containing        about 1:1 of HMS5552 and Eudragit L100;    -   about 2 mg of repaglinide;    -   about 0-95% of filler(s);    -   about 1-25% of binder(s);    -   about 1-8% of disintegrant(s);    -   about 0.5-3% of lubricant(s);    -   about 0-0.5% of glidant(s); and    -   about 0-5% of coating agent(s).

Solution 22. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about150 mg of the solid dispersion, about 1.00 mg of repaglinide, about79.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropylcellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg ofsodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 75 mg of HMS5552.

Solution 23. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about100 mg of the solid dispersion, about 2.00 mg of repaglinide, about128.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropylcellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg ofsodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 50 mg of HMS5552.

Solution 24. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of solution 18, comprising about50 mg of the solid dispersion, about 2.00 mg of repaglinide, about 132.0mg of microcrystalline cellulose, about 6.00 mg of hydroxypropylcellulose, about 6.00 mg of croscarmellose sodium, about 2.00 mg ofsodium dodecyl sulfate, about 2.00 mg of magnesium stearate and about6.00 mg of Opadry, wherein the solid dispersion contains about 1:1 ofHMS5552 and Eudragit L100, and contains about 25 mg of HMS5552.

Solution 25. A method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulation of anyone of solutions 1-24, comprising incorporating the active ingredientsinto one or more excipients for granulation, preferably further fillingthe obtained granule mixture into a vial, a sachet or a capsule, orcompressing it into a tablet with a desired shape; and more preferably,further coating the obtained tablet.

Solution 26. The method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulationaccording to solution 25, wherein the preparation is carried out by wetgranulation (high shear and/or fluidized bed), or by dry processing(direct compression or dry granulation).

Solution 27. The method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulationaccording to any one of solutions 25-26, wherein the glucokinaseactivator is prepared in the form of a solid dispersion.

Solution 28. The method for preparing the pharmaceutical combination,pharmaceutical composition, or fixed dose combination formulationaccording to any one of solutions 25-27, wherein the glucokinaseactivator and the second or more active ingredients can also be preparedtogether in the form of a combination solid dispersion (that is, a soliddispersion comprising two or more active ingredients).

Solution 29. The pharmaceutical combination, pharmaceutical composition,or fixed dose combination formulation of any one of solutions 1-24,which is used to prevent, slow the progression of, delay, or treat oneor more metabolic disorders selected from the group consisting of: typeI diabetes, type II diabetes, maturity-onset diabetes of the young(MODY), impaired glucose tolerance, impaired fasting blood glucose,hyperglycemia, postprandial hyperglycemia, overweight, obesity,hypertension, insulin resistance, diseases associated with isletdysfunction and/or metabolic syndrome; or improve blood glucose controland/or reduce fasting plasma glucose, postprandial plasma glucose and/orglycosylated hemoglobin HbA1c; or prevent, slow, delay, or reversecomplications of diabetes mellitus.

Solution 30. A method for preventing, slowing the progression of,delaying, or treating one or more metabolic disorders selected from thegroup consisting of: type I diabetes, type II diabetes, maturity-onsetdiabetes of the young (MODY), impaired glucose tolerance, impairedfasting blood glucose, hyperglycemia, postprandial hyperglycemia,overweight, obesity, hypertension, insulin resistance, diseasesassociated with islet dysfunction and/or metabolic syndrome; orimproving blood glucose control and/or reducing fasting plasma glucose,postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; orpreventing, slowing, delaying, or reversing complications of diabetesmellitus, comprising administering to a subject a therapeuticallyeffective amount of the pharmaceutical combination, pharmaceuticalcomposition or fixed dose combination formulation of any one ofsolutions 1-24.

Solution 31. Use of the pharmaceutical combination, pharmaceuticalcomposition or fixed dose combination formulation of any one ofsolutions 1-24 in the manufacture of a medicament for preventing,slowing the progression of, delaying, or treating one or more metabolicdisorders selected from the group consisting of: type I diabetes, typeII diabetes, maturity-onset diabetes of the young (MODY), impairedglucose tolerance, impaired fasting blood glucose, hyperglycemia,postprandial hyperglycemia, overweight, obesity, hypertension, insulinresistance, diseases associated with islet dysfunction and/or metabolicsyndrome; or improving blood glucose control and/or reducing fastingplasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin HbA1c.

The following examples further describe and illustrate embodimentswithin the scope of the present disclosure. However, the presentinvention is not limited to the examples, and various modifications andsubstitutions made on the basis of the technology disclosed herein arewithin the protection scope of the present invention.

EXAMPLES Preparation of the Combination Tablet of the GlucokinaseActivator

The chemicals used in the present disclosure can be purchased fromcompanies such as Shin-Etsu Japan, Evonik Germany, J.T. Baker US, SCRChina, Ashland US, FMC US, JRS Germany, Colorcon US, Capsugel, BASF,Zhenxing China, and the like. A producing equipment, analytical testinginstrument and the like can be purchased from companies such asSartorius, Nikon, Sympatec, Bruker, Gea Niro, Korsch, Erweka, Agilent,Quadro Engineering, Canada; Waters, US; TA, US; SOTAX, Switzerland;Mettler Toledo Instrument Newark, Del.

I. Preparation of the Solid Dispersion of the Glucokinase Activator 1.1Preparation of the Solution of the Solid Dispersion Used for SprayDrying Example 1A (Weight Ratio of Active Ingredients to PolymerCarriers is 1:9)

6.75 g Eudragit L100 (Evonik Germany) was weighed, and added toanhydrous ethanol (J.T.Baker) under stirring. After it was completelydissolved, 0.75 g of the compound HMS5552 was added. Stirring wascontinued after adding sufficient amount of anhydrous ethanol to obtain50 ml solution.

Example 2A (Weight Ratio of Active Ingredients to Polymer Carriers is3:7)

5.25 g Eudragit L100 (Evonik Germany) was weighed, and added toanhydrous ethanol (J.T.Baker) under stirring. After it was completelydissolved, 2.25 g of the compound HMS5552 was added. Stirring wascontinued after adding sufficient amount of anhydrous ethanol to obtain50 ml solution.

Example 3A (Weight Ratio of Active Ingredients to Polymer Carriers is5:5)

3.75 g Eudragit L100 (Evonik Germany) was weighed, and added toanhydrous ethanol (J.T.Baker) under stirring. After it was completelydissolved, 3.75 g of the compound HMS5552 was added. Stirring wascontinued after adding sufficient amount of anhydrous ethanol to obtain50 ml solution.

Example 4A (Weight Ratio of Active Ingredients to Polymer Carriers is7:3)

2.25 g Eudragit L100 (Evonik Germany) was weighed, and added toanhydrous ethanol (J.T.Baker) under stirring. After it was completelydissolved, 5.25 g of the compound HMS5552 was added. Stirring wascontinued after adding sufficient amount of anhydrous ethanol to obtain50 ml solution.

Example 5A (Weight Ratio of Active Ingredients to Polymer Carriers is8:2)

1.5 g Eudragit L100 (Evonik Germany) was weighed, and added to anhydrousethanol (J.T.Baker) under stirring. After it was completely dissolved, 6g of the compound HMS5552 was added. Stirring was continued after addingsufficient amount of anhydrous ethanol to obtain 50 ml solution.

Example 6A (Weight Ratio of Active Ingredients to Polymer Carriers is9:1)

0.75 g Eudragit L100 (Evonik Germany) was weighed, and added toanhydrous ethanol (J.T.Baker) under stirring. After it was completelydissolved, 6.75 g of the compound HMS5552 was added. Stirring wascontinued after adding sufficient amount of anhydrous ethanol to obtain50 ml solution.

Example 7A (Weight Ratio of Active Ingredients to Polymer Carriers is6:4)

3.0 g Eudragit L100 (Evonik Germany) was weighed, and added to anhydrousethanol (J.T.Baker) under stirring. After it was completely dissolved,4.5 g of the compound HMS5552 was added. Stirring was continued afteradding sufficient amount of anhydrous ethanol to obtain 50 ml solution.

Example 8A (Weight Ratio of Active Ingredients to Polymer Carriers is4:6)

4.5 g Eudragit L100 (Evonik Germany) was weighed, and added to anhydrousethanol (J.T.Baker) under stirring. After it was completely dissolved,3.0 g of the compound HMS5552 was added. Stirring was continued afteradding sufficient amount of anhydrous ethanol to obtain 50 ml solution.

Example 9A (Weight Ratio of Active Ingredients to Polymer Carriers is5:5)

187.5 g Eudragit L100 (Evonik Germany) was weighed, and added toanhydrous ethanol (Zhenxing China). After it was completely dissolved,187.5 g of the compound HMS5552 was added. Stirring was continued afteradding sufficient amount of anhydrous ethanol to obtain 2500 mlsolution.

1.2 Preparation of the solid dispersion of the glucokinase activator

The solid dispersion of the glucokinase activator was prepared by spraydrying the solution prepared above. The numbering of the obtained soliddispersion corresponds to the numbering of the above examples. The spraydrying devices that are suitable for the present disclosure include, butare not limited to, the spray drying devices produced by Niro GEAProcess Engineering Inc., Buchi Labortechnik AG, ProCept and SPXANHYDROUS companies. The spray drying can be performed by selecting anappropriate inlet air temperature of dry gas, inlet amount, feed rate,and atomization pressure, so that the droplets are sufficiently dried asthey reach the device wall. This can make sure that the dried dropletsare essentially solid and in a form of a fine powder, which will notstick to the wall, and is not difficult to collect in the cyclone. Theresulting powder is subjected to a secondary drying to make sure theproduct meets quality requirement.

Description of the Production Process for the Preparation of the SolidDispersion of the Glucokinase Activator by Spray Drying

The solid dispersions were prepared by the spray drying the solutionprepared in the above Examples 1A-8A, wherein the inlet air temperatureof the spray dryer was 90-150° C., the flow rate of the inlet air was0.3-0.5 m³/min, the flow rate of the air flow was 15-30 L/min, and thespray rate of above solutions were 5-7 mL/min. Solid dispersions 1-8were obtained by spray drying.

The solid dispersion was prepared by spray drying the solution preparedin the above Example 9A, wherein the inlet air temperature of the spraydryer was 90-150° C., the flow rate of the inlet air was 20-30 kg/h, theflow rate of the air flow was 3-30 kg/h, and the spray rate of abovesolutions were 5-200 mL/min. Solid dispersion 9 was obtained by spraydrying.

Solid dispersions 1-9 were prepared according to the process describedabove, wherein:

mass percent of the compound HMS5552 in solid dispersion 1 was 10%; masspercent of the compound HMS5552 in solid dispersion 2 was 30%; masspercent of the compound HMS5552 in solid dispersion 3 was 50%; masspercent of the compound HMS5552 in solid dispersion 4 was 70%; masspercent of the compound HMS5552 in solid dispersion 5 was 80%; masspercent of the compound HMS5552 in solid dispersion 6 was 90%; masspercent of the compound HMS5552 in solid dispersion 7 was 60%; masspercent of the compound HMS5552 in solid dispersion 8 was 40%; and masspercent of the compound HMS5552 in solid dispersion 9 was 50%.

II. Preparation of the Combination Tablet 2.1 Preparation of theCombination Tablet by High-Shear Wet Granulation

The HMS5552 solid dispersion prepared according to the above preparationexamples of the solid dispersion of the glucokinase activator and thepartner drug were added into a high-shear wet granulator. The filler(e.g., microcrystalline cellulose, silicified microcrystallinecellulose, or lactose) and disintegrant (e.g., croscarmellose sodium,crospovidone, or sodium starch glycolate) were added. A part of thebinder powder was added and mixed for 5 minutes with high-shearstirring. A prepared solution of the binder (e.g., hydroxypropylcellulose, polyvinylpyrrolidone or hydroxypropyl methyl cellulose) wasadded to the above dry mixture under high-shear stirring for 1 to 6minutes for granulation. Wet granules are sized on a Comil mill toobtain wet granules of suitable size. The wet granules were dried with atray in an oven at about 60° C. or in a fluidized bed dryer (with theinlet air temperature of 40-60° C.) for 20-40 minutes. Then, the driedmaterial was ground using a grinder to obtain granules of suitable size.After grinding, the microcrystalline cellulose or silicifiedmicrocrystalline cellulose (for the filler comprising an extragranularpart) and the disintegrant (e.g., croscarmellose sodium, crospovidone,or sodium starch glycolate) were added to the granules and the mixturewas mixed in a barrel mixer. Then, the lubricant (magnesium stearate orsodium stearyl fumarate) and/or optional glidant (micronized silica gel)were added to the mixture and mixed well additionally. The lubricatedmixture was compressed with a rotary tablet press to obtain tablets(plain tablets, uncoated tablet cores) of different tablet weights andtablet shapes corresponding to different strengths. Optionally, theobtained tablets were film-coated with Opadry® II, and the weightincreased by about 3%, thereby obtaining film-coated tablets.

Example 1B A Combination Tablet of HMS5552+Glimepiride (Dose Strength:50 mg/1 mg)

Formula composition Unit formula amount/mg % (w/w) Glimepiride 1.00 0.40HMS5552 solid dispersion* 100.00 40.00 Microcrystalline cellulose 129.0051.60 Hydroxypropyl cellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00Sodium dodecyl sulfate 2.50 1.00 Magnesium stearate 2.50 1.00 Totalweight of a tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of acoated tablet 257.50 — *100.00 mg of the HMS5552 solid dispersioncontained 50 mg of HMS5552.

Example 2B A Combination Tablet of HMS5552+Glimepiride (Dose Strength:75 mg/1 mg)

Formula composition Unit formula amount/mg % (w/w) Glimepiride 1.00 0.40HMS5552 solid dispersion* 150.00 60.00 Microcrystalline cellulose 79.0031.60 Hydroxypropyl cellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00Sodium dodecyl sulfate 2.50 1.00 Magnesium stearate 2.50 1.00 Totalweight of a tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of acoated tablet 257.50 — *150.00 mg of the HMS5552 solid dispersioncontained 75 mg of HMS5552.

Example 3B A Combination Tablet of HMS5552+Glimepiride (Dose Strength:100 mg/1 mg

Formula composition Unit formula amount/mg % (w/w) Glimepiride 1.00 0.40HMS5552 solid dispersion* 200.00 80.00 Microcrystalline cellulose 29.0011.60 Hydroxypropyl cellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00Sodium dodecyl sulfate 2.50 1.00 Magnesium stearate 2.50 1.00 Totalweight of a tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of acoated tablet 257.50 — *200.00 mg of the HMS5552 solid dispersioncontained 100 mg of HMS5552.

Example 4B A Combination Tablet of HMS5552+Glimepiride (Dose Strength:50 mg/2 mg)

Formula composition Unit formula amount/mg % (w/w) Glimepiride 2.00 0.80HMS5552 solid dispersion* 100.00 40.00 Microcrystalline cellulose 128.0051.20 Hydroxypropyl cellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00Sodium dodecyl sulfate 2.50 1.00 Magnesium stearate 2.50 1.00 Totalweight of a tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of acoated tablet 257.50 — *100.00 mg of the HMS5552 solid dispersioncontained 50 mg of HMS5552.

Example 5B A Combination Tablet of HMS5552+Glimepiride (Dose Strength:75 mg/2 mg)

Formula composition Unit formula amount/mg % (w/w) Glimepiride 2.00 0.80HMS5552 solid dispersion* 150.00 60.00 Microcrystalline cellulose 78.0031.20 Hydroxypropyl cellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00Sodium dodecyl sulfate 2.50 1.00 Magnesium stearate 2.50 1.00 Totalweight of a tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of acoated tablet 257.50 — *150.00 mg of the HMS5552 solid dispersioncontained 75 mg of HMS5552.

Example 6B A Combination Tablet of HMS5552+Repaglinide (Dose Strength:75 mg/1 mg)

Formula composition Unit formula amount/mg % (w/w) Repaglinide 1.00 0.40HMS5552 solid dispersion* 150.00 60.00 Microcrystalline cellulose 79.0031.60 Hydroxypropyl cellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00Sodium dodecyl sulfate 2.50 1.00 Magnesium stearate 2.50 1.00 Totalweight of a tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of acoated tablet 257.50 — *150.00 mg of the HMS5552 solid dispersioncontained 75 mg of HMS5552.

Example 7B A Combination Tablet of HMS5552+Repaglinide (Dose Strength:50 mg/2 mg)

Formula composition Unit formula amount/mg % (w/w) Repaglinide 2.00 0.80HMS5552 solid dispersion* 100.00 40.00 Microcrystalline cellulose 128.0051.20 Hydroxypropyl cellulose 7.50 3.00 Croscarmellose sodium 7.50 3.00Sodium dodecyl sulfate 2.50 1.00 Magnesium stearate 2.50 1.00 Totalweight of a tablet core 250.00 100.00 Opadry 7.50 3.00 Total weight of acoated tablet 257.50 — *100.00 mg of the HMS5552 solid dispersioncontained 50 mg of HMS5552.

2.2 Preparation of the Combination Tablet by Fluidized Bed WetGranulation

The HMS5552 solid dispersion prepared according to the above preparationexamples of the solid dispersion of the glucokinase activator and thepartner drug were added into a fluidized bed granulator. The optionalfiller (e.g., microcrystalline cellulose) was added. The preparedsolution of the binder (e.g., polyvinylpyrrolidone) was sprayed into themixture in the fluidized bed during 20 to 60 minutes for granulation,and then drying was continued in a fluidized bed dryer (with the inletair temperature of 40-60° C.). Then, the dried material was ground usinga grinder to obtain granules of suitable size. After grinding, themicrocrystalline cellulose or silicified microcrystalline cellulose (forthe formulation comprising an extragranular filler) was added to thegranules, and the mixture was mixed in a barrel mixer. Then, thelubricant (magnesium stearate) and/or optional glidant (micronizedsilica gel) were added to the mixture and mixed well additionally. Thelubricated mixture was compressed with a rotary tablet press to obtaintablets (plain tablets, uncoated tablet cores) of different tabletweights and tablet shapes corresponding to different strengths.Optionally, the obtained tablets were film-coated according to the abovepreparation examples of the solid dispersion of the glucokinaseactivator, and the weight increased by about 3%, thereby obtainingfilm-coated tablets.

2.3 Preparation of the Combination Tablet by Dry Rolling Granulation

The HMS5552 solid dispersion prepared according to the above preparationexamples of the solid dispersion of the glucokinase activator and thepartner drug were added into a mixing tank. The filler (e.g.,microcrystalline cellulose) and the binder (e.g., hydroxypropylcellulose) were added and mixed well. Then, the mixture was rolled by aroller compaction granulator, and the obtained bar was crushed and sizedby a crusher to obtain granules of suitable size. After grinding, theoptional microcrystalline cellulose or silicified microcrystallinecellulose (for the filler comprising an extragranular part) and thedisintegrant (e.g., croscarmellose sodium) were added to the granules,and the mixture was mixed in a barrel mixer. Then, the lubricant(magnesium stearate or sodium stearyl fumarate) and/or optional glidant(micronized silica gel) were added to the mixture and mixed welladditionally. The lubricated mixture was compressed with a rotary tabletpress to obtain tablets (plain tablets, uncoated tablet cores) ofdifferent tablet weights and tablet shapes corresponding to differentstrengths. Optionally, the obtained tablets were film-coated withOpadry® II, and the weight increased by about 3%, thereby obtainingfilm-coated tablets.

Example 8B A Combination Tablet of HMS5552+Repaglinide (Dose Strength:25 mg/2 mg)

Formula composition Unit formula amount/mg % (w/w) Repaglinide 2.00 1.00HMS5552 solid dispersion* 50.00 25.0 Microcrystalline cellulose 132.0066.0 Hydroxypropyl cellulose 6.00 3.00 Croscarmellose sodium 6.00 3.00Sodium dodecyl sulfate 2.00 1.00 Magnesium stearate 2.00 1.00 Totalweight of a tablet core 200 100.00 Opadry 6.00 3.00 Total weight of acoated tablet 206.00 — *50.00 mg of the HMS5552 solid dispersioncontained 25 mg of HMS5552.

2.4 Preparation of the Combination Tablet by Direct Compression of thePowder Mixture

The HMS5552 solid dispersion prepared according to the above preparationexamples of the solid dispersion of the glucokinase activator and thepartner drug were premixed uniformly according to the principle ofgeometric progression, and then added to a mixing tank. The filler(e.g., microcrystalline cellulose), the disintegrant (e.g.,croscarmellose sodium) and optional glidant (micronized silica gel) wereadded to the granules and mixed in a barrel mixer. Then, the lubricant(magnesium stearate or sodium stearyl fumarate) was added to the mixtureand mixed well additionally. The lubricated mixture was compressed witha rotary tablet press to obtain tablets (plain tablets, uncoated tabletcores) of different tablet weights and tablet shapes corresponding todifferent strengths. Optionally, the obtained tablets were film-coatedwith Opadry® II, and the weight increased by about 3%, thereby obtainingfilm-coated tablets.

The formula composition of the combination tablet described in the abovepreparation process was:

Example 9B A Combination Tablet of HMS5552+Glimepiride (Dose Strength:25 mg/2 mg)

Formula composition Unit formula amount/mg % (w/w) Glimepiride 2.00 1.00HMS5552 solid dispersion* 50.00 25.00 Microcrystalline cellulose 136.0068.00 Hydroxypropyl cellulose 4.00 2.00 Croscarmellose sodium 4.00 2.00Sodium dodecyl sulfate 2.00 1.00 Magnesium stearate 2.00 1.00 Totalweight of a tablet core 200.00 100.00 Opadry 6.00 3.00 Total weight of acoated tablet 206.00 — *50.00 mg of the HMS5552 solid dispersioncontained 25 mg of HMS5552.

III. Dissolution Test In Vitro of the Combination Formulation Comprisingthe Glucokinase Activator

The dissolution rate of the tablet was tested by the paddle method ofthe Chinese Pharmacopoeia (2015 edition). The dissolution of HMS5552 andanother partner drug in the medium of pH 6.8 was tested, respectively.At 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes,respectively, 5 ml of samples were taken for HPLC analysis.

According to the above test method, several tablets of above-mentionedfixed dose strengths and their corresponding single tablets were testedfor their dissolution, and the results were shown below.

TABLE 1 The dissolution results of the fixed dose combination tabletsprepared in Example 7B Dissolution rate (%) Time point 5 min 15 min 30min 45 min 60 min Example 68.4 88.6 93.8 95.4 97.4 7B-HMS5552, 50 mgExample 53.7 73.9 82.4 86.9 90.0 7B-repaglinide, 2 mg

TABLE 2 The dissolution results of the fixed dose combination tabletsprepared in Example 8B Dissolution rate (%) Time point 5 min 15 min 30min 45 min 60 min Example 32.7 77.6 86.6 89.1 91.5 8B-HMS5552, 25 mgExample 25.7 62.4 74.3 79.9 83.9 8B-repaglinide, 2 mg

It can be seen from the above dissolution results of the fixed dosecombination formulations that the dissolution of the fixed dosecombination formulations disclosed herein meets the requirements of afast-release formulation.

IV. Physical Properties of the Combination Formulations Containing theGlucokinase Activator

According to the relevant instruments and methods described in thePharmacopoeia, the physical properties of several tablets ofabove-mentioned fixed-dose strengths were tested. The results weredescribed below.

TABLE 3 Physical properties of the fixed dose combination tablet coresprepared in different examples Item A combination tablet ofHMS5552/glimepiride, mg Dose strength 50/1 75/1 100/1 50/2 75/2 25/2Corresponding Example 1B 2B 3B 4B 5B 9B Tablet shape Round Round RoundRound Round Round biconvex biconvex biconvex biconvex biconvex biconvexTablet core size/mm 9.00 9.00 9.00 9.00 9.00 9.00 Colour white whitewhite white white white Weight/mg 250 250 250 250 250 200 Hardness/kp(average value) ≥7 ≥7 ≥7 ≥7 ≥7 ≥7 Disintegration time/minute ≤10 ≤10 ≤10≤10 ≤10 ≤10 Fragility/% ≤0.5 ≤0.5 ≤0.5 ≤0.5 ≤0.5 ≤0.5

TABLE 4 Physical properties of the fixed dose combination tablet coresprepared in different examples Item A combination tablet ofHMS5552/repaglinide, mg Dose strength 75/1 50/2 25/2 CorrespondingExample 6B 7B 8B Tablet shape Round Round Round biconvex biconvexbiconvex Tablet core 9.00 9.00 9.00 size/mm Colour white white whiteWeight/mg 300 300 400 Hardness/kp ≥10 ≥10 ≥10 (average value)Disintegration ≤10 ≤10 ≤10 time/minute Fragility/% ≤0.5 ≤0.5 ≤0.5

V. Study on Pharmacodynamics of the Combination Formulations Comprisingthe Glucokinase Activator Example 1C Study on the Effect of theCombination of the Glucokinase Activator and the Partner Drug onGlucose/Sucrose Tolerance in Normal Mice

Normal male C57BL/6J mice, after being fasted for 6 hours, were orallyadministered solvent control, 1 mg/kg of repaglinide, or a combinationof 10 mg/kg of HMS5552 and 1 mg/kg of repaglinide, respectively; andafter 1 hour, were orally given 2 g/kg of glucose. Blood was taken fromthe tail vein before being administered (−60 minutes), before beinggiven the glucose (0 minutes), and at 15, 30, 60, and 120 minutes afterbeing given the glucose, and the glucose content in the whole blood wasdetermined. The area under the curve for blood glucose between 0 and 120minutes (AUC0-120 min, mmol/L*min) was analyzed and compared with thatof the solvent control group. The results showed that the hypoglycemiceffect of the combination of 10 mg/kg of HMS5552 and 1 mg/kg ofrepaglinide is significantly better than that of the monotherapy of 1mg/kg of repaglinide, with statistically significant difference ofP<0.001.

A sulfonylurea hypoglycemic agent and a glinide hypoglycemic agent areK-ATP channel blockers, which reduce blood glucose by promoting thesecretion of insulin by islet β cells, and are widely used clinically totreat type 2 diabetes. HMS5552, a novel glucokinase activator, canimprove pancreatic islet function in patients with type 2 diabetes,promote the secretion of incretin, reduce insulin resistance, and hasdual therapeutic effects of reducing fasting and postprandial bloodglucose. For type 2 diabetic patients whose blood glucose control by asulfonylurea hypoglycemic agent or a glinide hypoglycemic agent fails,the combination of a sulfonylurea hypoglycemic agent or a glinidehypoglycemic agent and HMS5552 has better efficacy of blood glucosecontrol and reduces the risk of diabetes complications.

The above study on the effectiveness of HMS5552 combined with theexisting oral diabetes drug shows that the combined use can improve theefficacy of HMS5552 or existing hypoglycemic drugs, reduce safety risks,and improve medical effects. Oral fixed dose combination formulationsdeveloped with HMS5552 and existing oral diabetes drugs are currentlythe most promising combination drugs for diabetes treatment to solve theabove clinical needs.

What is claimed is:
 1. A pharmaceutical combination, comprising: (a) a glucokinase activator, wherein the glucokinase activator is a compound represented by the following formulae, or a pharmaceutically acceptable salt, an isotope labeled analogue, a crystalline form, a hydrate, a solvate, or a diastereomeric or enantiomeric form thereof,

(b) a K-ATP channel blocker; wherein the above-mentioned drugs (a) and (b) are used simultaneously, separately or sequentially.
 2. The pharmaceutical combination of claim 1, wherein the weight ratio of the glucokinase activator to the K-ATP channel blocker is about 400:1 to 10:1, preferably about 100:1 to 25:2, or more preferably about 25:2, about 25:1, about 50:1, about 75:2, about 75:1, or about 100:1.
 3. The pharmaceutical combination of claim 1 or 2, wherein the glucokinase activator is the compound HMS5552 represented by the following formula, or an isotope labeled analogue or a pharmaceutically acceptable salt thereof,


4. The pharmaceutical combination of any one of claims 1-3, wherein the glucokinase activator is in the form of a solid dispersion; or preferably, the glucokinase activator is in the form of a solid dispersion containing a polymer carrier, wherein the polymer carrier is methacrylic acid copolymer of type A (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, or more preferably Eudragit L100.
 5. The pharmaceutical combination of claim 4, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, or more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6.
 6. The pharmaceutical combination of any one of claims 1 to 5, wherein the K-ATP channel blocker is selected from the group consisting of sulfonylurea secretagogues including glibenclamide, glipizide, gliclazide, gliquidone and glimepiride, and a pharmaceutically acceptable salt thereof; or selected from the group consisting of non-sulfonylurea insulin secretagogues including repaglinide and nateglinide, and a pharmaceutically acceptable salt thereof.
 7. The pharmaceutical combination of any one of claims 1 to 6, wherein the glucokinase activator is present in a dose (preferably, a unit dose) ranging from about 1 mg to about 200 mg, or preferably about 25 mg to about 100 mg, preferably, wherein the dose (preferably, a unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg, or about 100 mg.
 8. The pharmaceutical combination of any one of claims 1-7, wherein the K-ATP channel blocker is present in a dose (preferably, a unit dose) ranging from about 0.1 mg to about 10 mg, or preferably about 1 mg to about 5 mg, preferably, wherein the dose (preferably, a unit dose) of the K-ATP channel blocker is about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 4 mg or about 5 mg, or still preferably about 1 mg or about 2 mg; and preferably, the K-ATP channel blocker is glimepiride or repaglinide.
 9. The pharmaceutical combination of any one of claims 1-8, which is in the form of a pharmaceutical composition.
 10. The pharmaceutical composition of claim 9, comprising the K-ATP channel blocker and a solid dispersion of the glucokinase activator, preferably, wherein the weight ratio of the solid dispersion of the glucokinase activator to the K-ATP channel blocker is about 400:1 to 20:1, preferably about 200:1 to 25:1, or more preferably about 25:1, about 50:1, about 100:1, about 75:1, about 150:1 or about 200:1.
 11. The pharmaceutical composition of claim 9 or 10, wherein the solid dispersion of the glucokinase activator is about 1-99% by weight; and the K-ATP channel blocker is about 0.1-15% by weight.
 12. The pharmaceutical composition of any one of claims 9-11, further comprising one or more excipients, preferably, wherein the excipients are selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweetening agents, coloring agents and coating agents.
 13. The pharmaceutical composition of any one of claims 9-12, which is in a form selected from the group consisting of a tablet, a capsule, a pill and a lozenge, preferably a tablet, or more preferably a coated tablet.
 14. A fixed dose combination formulation, comprising: (a) a glucokinase activator, which is a compound represented by the following formulae, or a pharmaceutically acceptable salt, an isotope labeled analogue, a crystalline form, a hydrate, a solvate, or a diastereomeric or enantiomeric form thereof,

(b) a K-ATP channel blocker; and (c) one or more excipients.
 15. The fixed dose combination formulation of claim 14, wherein the weight ratio of the glucokinase activator to the K-ATP channel blocker is about 200:1 to 10:1, preferably about 100:1 to 25:2, or more preferably about 25:2, about 25:1, about 50:1, about 75:2, about 75:1, or about 100:1.
 16. The fixed dose combination formulation of claim 14 or 15, wherein the glucokinase activator is about 1-99% by weight; and the K-ATP channel blocker is about 0.1-15% by weight.
 17. The fixed dose combination formulation of any one of claims 14-16, wherein the glucokinase activator is the compound HMS5552 represented by the following formula, or an isotope labeled analogue or a pharmaceutically acceptable salt thereof,


18. The fixed dose combination formulation of any one of claims 14-17, wherein the glucokinase activator is in the form of a solid dispersion, preferably, wherein the glucokinase activator is in the form of a solid dispersion containing a polymer carrier, and the polymer carrier is methacrylic acid copolymer of type A (an anionic copolymer of methacrylic acid and methyl methacrylate (1:1)), preferably Eudragit, or more preferably Eudragit L100.
 19. The fixed dose combination formulation of any one of claims 14-18, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, preferably about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4 or about 5:6 to 6:5, or more preferably about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6.
 20. The fixed dose combination formulation of any one of claims 14-19, wherein the K-ATP channel blocker is selected from the group consisting of sulfonylurea secretagogues including glibenclamide, glipizide, gliclazide, gliquidone and glimepiride, and a pharmaceutically acceptable salt thereof; or selected from the group consisting of non-sulfonylurea insulin secretagogues including repaglinide and nateglinide, and a pharmaceutically acceptable salt thereof.
 21. The fixed dose combination formulation of any one of claims 14-20, wherein the glucokinase activator is present in a dose (preferably, a unit dose) ranging from about 1 mg to about 200 mg, or preferably about 25 mg to about 100 mg, preferably, wherein the dose (preferably, a unit dose) of the glucokinase activator is about 25 mg, about 50 mg, about 75 mg or about 100 mg.
 22. The fixed dose combination formulation of any one of claims 14-21, wherein the K-ATP channel blocker is present in a dose (preferably, a unit dose) ranging from about 0.1 mg to about 10 mg, or preferably about 1 mg to about 5 mg, preferably, wherein the dose (preferably, a unit dose) of the K-ATP channel blocker is about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 4 mg or about 5 mg, or still preferably about 1 mg or about 2 mg; and preferably, the K-ATP channel blocker is glimepiride or repaglinide.
 23. The fixed dose combination formulation of any one of claims 14-22, wherein the weight ratio of the solid dispersion of the glucokinase activator to the K-ATP channel blocker is about 400:1 to 20:1, preferably about 200:1 to 25:1, or more preferably about 25:1, about 50:1, about 100:1, about 75:1, about 150:1, or about 200:1.
 24. The fixed dose combination formulation of claim 23, wherein the glucokinase activator is about 1-99% by weight; and the K-ATP channel blocker is about 0.1-15% by weight.
 25. The fixed dose combination formulation of any one of claims 14-24, wherein the one or more excipients are selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweetening agents, coloring agents and coating agents.
 26. The fixed dose combination formulation of claim 25, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the filler is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch and pregelatinized starch; the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate; the lubricant is selected from the group consisting of magnesium stearate and sodium stearyl fumarate; and the glidant is selected from the group consisting of colloidal silicon dioxide and talc.
 27. The fixed dose combination formulation of any one of claims 14-26, which is a tablet.
 28. The fixed dose combination formulation of claim 27, which is a coated tablet.
 29. The fixed dose combination formulation of claim 28, wherein the coated tablet is a film-coated tablet, wherein the film-coating agent comprises: film-coating substrate(s), such as hypromellose, hydroxypropyl methyl cellulose, or a mixture thereof; optional plasticizer(s), such as polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or a mixture thereof; optional coloring agent(s), such as iron oxide red, iron oxide yellow, or a mixture thereof; optional opacifier(s), such as titanium dioxide, and optional glidant(s).
 30. The fixed dose combination formulation of claim 29, wherein the coated tablet is a film-coated tablet, and the film-coating agent is Opadry.
 31. The fixed dose combination formulation of any one of claims 14-30, comprising (by weight): about 1-99% of the glucokinase activator, preferably HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 0.1-15% of the K-ATP channel blocker; about 0-80% of filler(s); about 1-25% of binder(s); about 0-15% of disintegrant(s); about 0.1-10% of lubricant(s); about 0-3% of glidant(s); and about 0-5% of coating agent(s).
 32. The fixed dose combination formulation of claim 31, wherein the doses (preferably, unit doses) of the active ingredients are (by weight): about 25 mg, about 50 mg, about 75 mg or about 100 mg of the glucokinase activator, or preferably HMS5552; and about 1 mg, about 2 mg, or about 4 mg of glimepiride.
 33. The fixed dose combination formulation of claim 32, which is a tablet of 50 mg HMS5552/1 mg glimepiride, and comprises the components with the following amounts (by weight): about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 1 mg of glimepiride; about 0-80% of filler(s); about 2-8% of binder(s); about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 34. The fixed dose combination formulation of claim 32, which is a tablet of 75 mg HMS5552/1 mg glimepiride, and comprises the components with the following amounts (by weight): about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 1 mg of glimepiride; about 0-80% of filler(s); about 2-8% of binder(s); about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 35. The fixed dose combination formulation of claim 32, which is a tablet of 100 mg HMS5552/1 mg glimepiride, and comprises the components with the following amounts (by weight): about 100 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 1 mg of glimepiride; about 0-80% of filler(s); about 2-8% of binder(s); about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 36. The fixed dose combination formulation of claim 32, which is a tablet of 25 mg HMS5552/2 mg glimepiride, and comprises the components with the following amounts (by weight): about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 2 mg of glimepiride; about 0-80% of filler(s); about 2-8% of binder(s); about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 37. The fixed dose combination formulation of claim 32, which is a tablet of 50 mg HMS5552/2 mg glimepiride, and comprises the components with the following amounts (by weight): about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 2 mg of glimepiride; about 0-80% of filler(s); about 2-8% of binder(s); about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 38. The fixed dose combination formulation of claim 32, which is a tablet of 75 mg HMS5552/2 mg glimepiride, and comprises the components with the following amounts (by weight): about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 2 mg of glimepiride; about 0-80% of filler(s); about 2-8% of binder(s); about 1-5% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 39. The fixed dose combination formulation of claim 32, comprising about 100 mg of the solid dispersion, about 1.00 mg of glimepiride, about 129.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 50 mg of HMS5552.
 40. The fixed dose combination formulation of claim 32, comprising about 150 mg of the solid dispersion, about 1.00 mg of glimepiride, about 79.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 75 mg of HMS5552.
 41. The fixed dose combination formulation of claim 32, comprising about 200 mg of the solid dispersion, about 1.00 mg of glimepiride, about 29.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 100 mg of HMS5552.
 42. The fixed dose combination formulation of claim 32, comprising about 100 mg of the solid dispersion, about 2.00 mg of glimepiride, about 128.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 50 mg of HMS5552.
 43. The fixed dose combination formulation of claim 32, comprising about 150 mg of the solid dispersion, about 2.00 mg of glimepiride, about 78.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 75 mg of HMS5552.
 44. The fixed dose combination formulation of claim 32, comprising about 50 mg of the solid dispersion, about 2.00 mg of glimepiride, about 136.00 microcrystalline cellulose, about 4.00 mg of hydroxypropyl cellulose, about 4.00 mg of croscarmellose sodium, about 2.00 mg of sodium dodecyl sulfate, about 2.00 mg of magnesium stearate, and about 6.00 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 25 mg of HMS5552.
 45. The fixed dose combination formulation of claim 31, wherein the doses (preferably, unit doses) of the active ingredients are (by weight): about 25 mg, about 50 mg, about 75 mg or about 100 mg of the glucokinase activator, or preferably HMS5552; and about 0.5 mg, about 1 mg, or about 2 mg of repaglinide.
 46. The fixed dose combination formulation of claim 45, which is a tablet of 75 mg HMS5552/1 mg repaglinide, and comprises the components with the following amounts (by weight): about 75 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 1 mg of repaglinide; about 0-95% of filler(s); about 1-25% of binder(s); about 1-8% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 47. The fixed dose combination formulation of claim 45, which is a tablet of 50 mg HMS5552/2 mg repaglinide, and comprises the components with the following amounts (by weight): about 50 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 2 mg of repaglinide; about 0-95% of filler(s); about 1-25% of binder(s); about 1-8% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 48. The fixed dose combination formulation of claim 45, which is a tablet of 25 mg HMS5552/2 mg repaglinide, and comprises the components with the following amounts (by weight): about 25 mg of HMS5552, preferably a solid dispersion of HMS5552, preferably a solid dispersion containing HMS5552 and a polymer carrier, or preferably a solid dispersion containing about 1:1 of HMS5552 and Eudragit L100; about 2 mg of repaglinide; about 0-95% of filler(s); about 1-25% of binder(s); about 1-8% of disintegrant(s); about 0.5-3% of lubricant(s); about 0-0.5% of glidant(s); and about 0-5% of coating agent(s).
 49. The fixed dose combination formulation of claim 45, comprising about 150 mg of the solid dispersion, about 1.00 mg of repaglinide, about 79.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 75 mg of HMS5552.
 50. The fixed dose combination formulation of claim 45, comprising about 100 mg of the solid dispersion, about 2.00 mg of repaglinide, about 128.00 mg of microcrystalline cellulose, about 7.50 mg of hydroxypropyl cellulose, about 7.50 mg of croscarmellose sodium, about 2.50 mg of sodium dodecyl sulfate, about 2.50 mg of magnesium stearate, and about 7.50 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 50 mg of HMS5552.
 51. The fixed dose combination formulation of claim 45, comprising about 50 mg of the solid dispersion, about 2.00 mg of repaglinide, about 132.00 mg of microcrystalline cellulose, about 6.00 mg of hydroxypropyl cellulose, about 6.00 mg of croscarmellose sodium, about 2.00 mg of sodium dodecyl sulfate, about 2.00 mg of magnesium stearate, and about 6.00 mg of Opadry, wherein the solid dispersion contains about 1:1 of HMS5552 and Eudragit L100, and contains about 25 mg of HMS5552.
 52. A method for preparing the fixed dose combination formulation of any one of the preceding claims, comprising incorporating the active ingredients into one or more excipients for granulation, preferably further filling the obtained granule mixture into a vial, a sachet or a capsule, or compressing it into a tablet with a desired shape; and more preferably, further coating the obtained tablet.
 53. The method for preparing the fixed dose combination formulation according to claim 52, wherein the preparation is carried out by wet granulation (high shear and/or fluidized bed), or by dry processing (direct compression or dry granulation).
 54. The method for preparing the fixed dose combination formulation according to any one of claims 52-53, wherein the glucokinase activator is prepared in the form of a solid dispersion.
 55. The method for preparing the fixed dose combination formulation according to any one of claims 52-54, wherein the glucokinase activator and the second or more active ingredients are prepared together in the form of a combination solid dispersion.
 56. The pharmaceutical combination or pharmaceutical composition of any one of claims 1-13 or the fixed dose combination formulation of any one of claims 14-51, which is used to prevent, slow the progression of, delay, or treat one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, maturity-onset diabetes of the young (MODY), impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diseases associated with islet dysfunction and/or metabolic syndrome; or improve blood glucose control and/or reduce fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; or prevent, slow, delay, or reverse complications of diabetes mellitus.
 57. A method for preventing, slowing the progression of, delaying, or treating one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, maturity-onset diabetes of the young (MODY), impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diseases associated with islet dysfunction and/or metabolic syndrome; or improving blood glucose control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c; or preventing, slowing, delaying, or reversing complications of diabetes mellitus, comprising administering to a subject a therapeutically effective amount of the pharmaceutical combination or pharmaceutical composition of any one of claims 1-13 or the fixed dose combination formulation of any one of claims 14-51.
 58. Use of the pharmaceutical combination or pharmaceutical composition of any one of claims 1-13 or the fixed dose combination formulation of any one of claims 14-51 in the manufacture of a medicament for preventing, slowing the progression of, delaying, or treating one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, maturity-onset diabetes of the young (MODY), impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diseases associated with islet dysfunction and/or metabolic syndrome; or improving blood glucose control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c. 